Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0013911 (emaciation)
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Nickel sulfate hexahydrate is used in nickel plating, as a mordant in dyeing and printing textiles, as a blackening agent for zinc and brass, and in the manufacture of organic nickel salts. Nickel sulfate hexahydrate was nominated by the National Cancer Institute to the NTP as part of a class study of nickel compounds for which there was little information on the toxic and carcinogenic effects of inhalation exposure. Male and female F344/N rats and B6C3F1 mice were exposed to nickel sulfate hexahydrate (greater than 98% pure) by inhalation for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in L5178Y mouse lymphoma cells. 16-DAY STUDY IN RATS: Groups of five male and five female F344/N rats were exposed to 0, 3.5, 7, 15, 30, or 60 mg nickel sulfate hexahydrate/m(3) (equivalent to 0, 0.7, 1.4, 3.1, 6.1, or 12.2 mg nickel/m(3)). Rats were exposed on weekdays only, for a total of 12 exposure days during a 16-day period. Additional groups of four or five male and female F344/N rats were exposed to 0, 3.5, 15, or 30 mg nickel sulfate hexahydrate/m(3)for tissue burden studies. In the core study, two 60 mg/m(3) males, one 30 mg/m(3) female, and all 60 mg/m(3)females died before the end of the study. Final mean body weights of all exposed groups of males and females were significantly lower than those of the controls, as were mean body weight gains of male rats. Clinical findings included increased rates of respiration and reduced activity levels in rats in all exposure groups, except those exposed to 3.5 mg/m(3). Absolute lung weights of 60 mg/m(3) males and of all exposed groups of females were significantly greater than those of the controls, as were the relative lung weights of all exposed groups of males and females. Inflammation (including degeneration and necrosis of the bronchiolar epithelium) occurred in the lungs of all exposed groups of males and females. Atrophy of the olfactory epithelium occurred in the nasal passages of all exposed groups of males (except 60 mg/m(3)) and in 15, 30, and 60 mg/m(3) females. Lymphoid hyperplasia in the bronchial or mediastinal lymph nodes was observed in 30 mg/m(3) males and in 60 mg/m(3) males and females. The concentration of nickel in the lungs of all exposed groups of males and females was greater than in control animals. 16-DAY STUDY IN MICE: Groups of five male and five female B6C3F1 mice were exposed to 0, 3.5, 7, 15, 30, or 60 mg nickel sulfate hexahydrate/m(3). Mice were exposed on weekdays only, for a total of 12 exposure days during a 16-day period. Additional groups of five male and five female B6C3F1 mice were exposed to 0 or 3.5 mg nickel sulfate hexahydrate/m(3)for tissue burden studies. All core study mice exposed to 7 mg/m(3) or greater died before the end of the study; all control and 3.5 mg/m(3)mice survived to the end of the study. Final mean body weights and weight gains of 7, 15, 30, and 60 mg/m(3)males and females were significantly less than those of the controls, and clinical findings in these groups included emaciation, lethargy, and rapid respiration rates. Absolute and relative lung weights of male and female mice exposed to 7 mg/m(3) or greater were significantly greater than those of the controls. Only tissues from mice exposed to 0, 3.5, or 7 mg/m(3) were examined histopathologically. Inflammation occurred in the lungs of 3.5 and 7 mg/m(3) males and females; necrosis of the alveolar and bronchiolar epithelium was a component of the inflammation in 7 mg/m(3)males and females. In addition, atrophy of the olfactory epithelium of the nasal passages was observed in 3.5 mg/m(3) males and females. Nickel concentrations in the lungs of mice exposed to 3.5 mg/m(3) were greater than those in the controls. 13-WEEK STUDY IN RATS: Groups of ten male and ten female F344/N rats were exposed to 0, 0.12, 0.25, 0.5, 1, or 2 mg nickel sulfate hexahydrate (equivalent to 0, 0.03, 0.06, 0.11, 0.22, or 0.44 mg nickel/m(3)), 5 days per week for 13 weeks. Additional groups of six male and six female F344/N rats were exposed to 0, 0.12, 0.5, or 2 mg nic mg nickel sulfate hexahydrate/m(3)for tissue burden studies. In the core study, one 2 mg/m(3)male rat died before the end of the study; all other males and all females survived until the end of the study. Final mean body weights and body weight gains of all exposed groups were similar to those of the controls. There were no significant clinical findings noted during the study. Exposure-related increases in neutrophil and lymphocyte numbers occurred and were most pronounced in female rats. With the exception of 0.12 mg/m(3)rats, absolute and relative lung weights of all exposed groups were generally significantly greater than those of the controls. Exposure-related increases in the incidence and severity of inflammatory lesions (alveolar macrophages, chronic inflammation, and interstitial infiltration) occurred in the lungs of all exposed groups of males and females. Lymphoid hyperplasia of the bronchial and/or mediastinal lymph nodes occurred in males exposed to 0.5 mg/m(3)or greater. Atrophy of the olfactory epithelium occurred in males and females exposed to 0.5, 1, and 2 mg/m(3)and in 0.25 mg/m(3)females. The concentration of nickel in the lungs of 0.5 and 2 mg/m(3) rats was greater than that in the lungs of control animals at 4, 9, and 13 weeks for males and at 13 weeks for females. 13-WEEK STUDY IN MICE: Groups of ten male and ten female B6C3F1 mice were exposed to 0, 0.12, 0.25, 0.5, 1, or 2 mg nickel sulfate hexahydrate, 5 days per week for 13 weeks. Additional groups of up to five or six male and female B6C3F1 mice were exposed to 0, 0.12, 0.5, or 2 mg nickel sulfate hexahydrate/m(3)for tissue burden studies. In the core study, four control males, three control females, and one 0.12 mg/m(3)male died before the end of the study; the deaths were not considered to be chemical related, and all other mice survived to the end of the study. The final mean body weights and body weight gains of all exposed groups were similar to those of the controls. There were no chemical-related clinical findings. Hematology changes similar to those reported in female rats occurred in female mice, but the mice were minimally affected. The absolute and relative lung weights of 1 mg/m(3)males and 2 mg/m(3)males and females were significantly greater than those of the controls. Increased numbers of alveolar macrophages occurred in all males and females exposed to 0.5 mg/m(3)or greater. Chronic active inflammation and fibrosis occurred in 1 and 2 mg/m(3)males and females. Lymphoid hyperplasia of the bronchial lymph node and atrophy of the olfactory epithelium in the nasal passages were observed in 2 mg/m(3)males and females. Nickel concentration in the lung of 2 mg/m(3)females was significantly greater than in control animals. 2-YEAR STUDY IN RATS: Groups of 63 to 65 male and 63 to 64 female rats were exposed to nickel sulfate hexahydrate by inhalation at concentrations of 0, 0.12, 0.25, or 0.5 mg/m(3) (equivalent to 0, 0.03, 0.06, or 0.11 mg nickel/m(3)). Animals were exposed for 6 hours plus T90 (8 minutes) 5 days per week for 104 weeks. Five male and five female rats from each group were evaluated at 7 months for histopathology; an additional seven males and seven females from each group were evaluated at 7 months for nickel tissue burden in the lung and kidney; and five males and five females from each group were evaluated at 15 months for alterations in hematology, nickel tissue burden in the lung and kidney, and histopathology. Survival, Body Weights, Clinical Findings, and Hematology The survival rates of all exposed groups of males and females were similar to those of the controls. Mean body weights of 0.5 mg/m(3)female rats were slightly lower (6% to 9%) than those of the controls throughout the second year of the study; final mean body weights of all exposed groups of males and 0.12 and 0.25 mg/m(3)females were similar to those of the controls. There were no clinical findings or hematology differences that were considered to be related to nickel sulfate hexahydrate administration. Pathology Findings No exposure-related neoplasms occurred in male or female rats exposed by inhalation to nickel sulfate hexahydrate for 2 years. Increased incidences of inflammatory lung lesions were generally observed in all exposed groups of male and female rats at the end of the study. The incidences of chronic active inflammation, macrophage hyperplasia, alveolar proteinosis, and fibrosis were markedly increased in male and female rats exposed to 0.25 or 0.5 mg/m(3). Increased incidences of lymphoid hyperplasia in the bronchial lymph nodes occurred in 0.5 mg/m(3)male and female rats at the end of the 2-year study. The incidences of atrophy of the olfactory epithelium in 0.5 mg/m(3)males and females were significantly greater than those in controls at the end of the study. Tissue Burden Analyses Lung nickel burdens in exposed male and female rats were greater than those in the controls at the 7- and 15-month interim evaluations, and lung nickel burdens values increased with increasing exposure concentration. 2-YEAR STUDY IN MICE: Groups of 80 male and 80 female mice were exposed to nickel sulfate hexahydrate by inhalation at concentrations of 0, 0.25, 0.5, or 1 mg/m(3) (equivalent to 0, 0.06, 0.11, or 0.22 mg nickel/m(3)). Animals were exposed for 6 hours plus T90 (8 minutes) 5 days per week for 104 weeks. Five male and five female mice from each group were evaluated at 7 months for histopathology; five males and five females from each group were evaluated at 7 months for nickel tissue burden in the lung and kidney; five males and five females from each group were evaluated at 15 months for alterations in hematology and histopathology; and five males and five females from each group were evaluated at 15 months for nickel tissue burden in the lung and kidney. Survival, Body Weights, Clinical Findings, and Hematology The survival rates of all exposed groups of males and females were similar to those of the controls. The mean body weights of 1 mg/m(3)males and of all exposed groups of females were lower than those of the controls during the second year of the study. There were no clinical findings or hematology differences considered to be related to chemical exposure. Pathology Findings Inflammatory lesions of the lung generally occurred in all exposed groups of male and female mice at the end of the 2-year study. These lesions included macrophage hyperplasia, chronic active inflammation, bronchialization (alveolar epithelial hyperplasia), alveolar proteinosis, and infiltrating cells in the interstitium. Incidences of macrophage hyperplasia and/or lymphoid hyperplasia occurred in the bronchial lymph nodes of most of the 1 mg/m(3)males and females and in some 0.5 mg/m(3)females at the end of the 2-year study. Atrophy of the olfactory epithelium was observed in 0.5 and 1 mg/m(3)males and in all exposed groups of females at the end of the 2-year study. Tissue Burden Analyses At the 7- and 15-month interim evaluations, lung nickel burden parameters measured in control and exposed groups were below the limit of detection. Absolute lung weights of 0.5 and 1 mg/m(3)lung burden study females were significantly greater than those of the controls at 15 months. GENETIC TOXICOLOGY: Nickel sulfate hexahydrate (500 to 800 g/mL) was tested for induction of trifluorothymidine resistance in L5178Y mouse lymphoma cells. A positive response was observed in the absence of S9. The test was not performed with S9. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was no evidence of carcinogenic activity of nickel sulfate hexahydrate in male or female F344/N rats exposed to 0.12, 0.25, or 0.5 mg/m(3) (0.03, 0.06, or 0.11 mg nickel/m(3)). There was no evidence of carcinogenic activity of nickel sulfate hexahydrate in male or female B6C3F1 mice exposed to 0.25, 0.5, or 1 mg/ m3 (0.06, 0.11, or 0.22 mg nickel/m(3)). Exposure of rats to nickel sulfate hexahydrate by inhalation for 2 years resulted in increased incidences of chronic active inflammation, macrophage hyperplasia, alveolar proteinosis, and fibrosis of the lung; lymphoid hyperplasia of the bronchial lymph node; and atrophy of the olfactory epithelium. Exposure of mice to nickel sulfate hexahydrate by inhalation for 2 years resulted in increased incidences of chronic active inflammation, bronchialization (alveolar epithelial hyperplasia), macrophage hyperplasia, interstitial infiltration, and alveolar proteinosis of the lung; lymphoid and macrophage hyperplasia of the bronchial lymph node; and atrophy of the olfactory epithelium. Synonyms: Blue salt; hexahydrate, nickel (2+) salt; nickel monosulfate hexahydrate; nickel (2+) sulfate hexahydrate; nickel (II) sulfate hexahydrate; nickel sulphate hexahydrate; nickelous sulfate hexahydrate; nickelous sulphate hexahydrate; single nickel salt, sulfuric acid
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PMID:NTP Toxicology and Carcinogenesis Studies of Nickel Sulfate Hexahydrate (CAS No. 10101-97-0) in F344 Rats and B6C3F1 Mice (Inhalation Studies). 1258 12

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