Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Toxicology and carcinogenesis studies were conducted by administering hydroquinone (more than 99% pure) by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 wk or 2 yr. 14-day studies were conducted by administering hydroquinone in corn oil to rats at doses ranging from 63 to 1000 mg/kg body weight and to mice at doses ranging from 31 to 500 mg/kg, 5 days/wk. In the 13-wk studies, doses for rats and mice ranged from 25 to 400 mg/kg. At those doses showing some indication of toxicity in the 14-day and 13-wk studies, the central nervous system, forestomach and liver were identified as target organs in both species and renal toxicity was observed in rats. Based on these results, 2-yr studies were conducted by administering 0, 25 or 50 mg hydroquinone/kg in deionized water by gavage to groups of 65 rats of each sex, 5 days/wk. Groups of 65 mice of each sex were given 0, 50 or 100 mg/kg on the same schedule. 10 rats and 10 mice from each group were killed and evaluated after 15 months. Mean body weights of high-dose male rats and high-dose mice were approx. 5-14% lower than those of controls during the second half of the study. No differences in survival were observed between dosed and control groups of rats or mice. Nearly all male rats and most female rats in all vehicle control and exposed groups had nephropathy, which was judged to be more severe in high-dose male rats. Hyperplasia of the renal pelvic transitional epithelium and renal cortical cysts were increased in male rats. Tubular cell hyperplasia of the kidney was seen in two high-dose male rats, and renal tubular adenomas were seen in 4/55 low-dose and 8/55 high-dose male rats; none was seen in vehicle controls or in female rats. Mononuclear cell leukaemia in female rats occurred with increased incidences in the dosed groups (vehicle control, 9/55; low dose, 15/55; high dose, 22/55). Compound-related lesions observed in the liver of high-dose male mice included anisokaryosis, syncytial alteration and basophilic foci. The incidences of hepatocellular neoplasms, primarily adenomas, were increased in dosed female mice (3/55; 16/55; 13/55). Follicular cell hyperplasia of the thyroid gland was increased in dosed mice.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Toxicity and carcinogenicity of hydroquinone in F344/N rats and B6C3F1 mice. 792 84

Hyperplasia of the thymus is a normal physiologic response in infants and children during recovery from life-threatening illness. New, recurrent, or residual mediastinal masses in children treated for malignant disease present a diagnostic dilemma. Are these masses recurrent disease or simply normal reactive thymic hyperplasia? Our experience from 1979 to 1986 includes 14 children aged 1 to 17 years (mean 7.4 years) who were identified with new or recurrent mediastinal masses during or after chemotherapeutic treatment for malignant disease (lymphoma 9, Wilms tumor 2, leukemia 1, osteosarcoma 1, malignant teratoma 1). The mediastinal masses were treated by a variety of methods depending on the attending physician's preference (close observation 2, oral steroids 5, steroids and subsequent biopsy 1, open biopsy 6). Chest roentgenograms of "observation only" patients have showed stable mediastinal changes without clinical evidence of recurrent disease. Patients treated with steroids showed resolution of the mediastinal masses in 48 hours to seven days, without recurrence. Patients undergoing open biopsy showed only thymic hyperplasia and/or lymph nodes. We suggest a stepwise approach to evaluation of these patients. Mediastinal masses occurring during, or shortly following, chemotherapeutic treatments of malignant disease should first be treated with oral prednisone (60 mg/m2/d x 7 to 10 d). If the patient shows a complete or partial resolution, then follow-up includes frequent chest roentgenograms and/or a second course of steroids. If the mass fails to respond to steroids, or enlarges, then open biopsy through a minithoractomy will clarify the diagnosis. Follow-up of our patients is from 3 months to 7 1/2 years (mean 5 years).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mediastinal mass following chemotherapeutic treatment of Hodgkin's disease: recurrent tumor or thymic hyperplasia? 344 Sep 3

Indium phosphide is used to make semiconductors,injection lasers, solar cells, photodiodes, and light-emittingdiodes. Indium phosphide was nominated for study because of its widespread use in the microelectronics industry, the potential for worker exposure,and the absence of chronic toxicity data. Male and female F344/N rats and B6C3F1 mice were exposed to indium phosphide (greater than 99% pure) by inhalation for 14 weeks or 2 years. The frequency of micronuclei was determined in the peripheral blood of mice exposed to indium phosphide for 14 weeks. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to particulate aerosols of indium phosphide with amass median aerodynamic diameter of approximately 1.2 microm at concentrations of 0, 1, 3, 10, 30, or 100 mg/m3 by inhalation, 6 hours per day, 5 days per week (weeks 1 through 4 and weeks 10 through 14) or 7 days per week (weeks 5 through 9) to accommodate a concurrent teratology study. One male in the 100 mg/m3 group died before the end of the study. Body weight gains of all males and females exposed to 100 mg/m3 were less than those of the chamber controls. As a result of indium phosphide exposure, the lungs of all exposed rats had a gray to black discoloration and were significantly enlarged, weighing 2.7- to 4.4-fold more than those of the chamber controls. Indium phosphide particles were observed throughout the respiratory tract and in the lung-associated lymph nodes. A spectrum of inflammatory and proliferative lesions generally occurred in the lungs of all exposed groups of rats and consisted of alveolar proteinosis, chronic inflammation, interstitial fibrosis, and alveolar epithelial hyperplasia. Pulmonary inflammation was attended by increased leukocyte and neutrophil counts in the blood. The alveolar proteinosis was the principal apparent reason for the increase in lung weights. Indium phosphide caused inflammation at the base of the epiglottis of the larynx and hyperplasia of the bronchial and mediastinal lymph nodes. Exposure to indium phosphide affected the circulating erythroid mass. It induced a microcytic erythrocytosis consistent with bone marrow hyperplasia and hematopoietic cell proliferation of the spleen. Hepatocellular necrosis was suggested by increased serum activities of alanine aminotransferase and sorbitol dehydrogenase in all exposed groups of males and in 10 mg/m3 or greater females and was confirmed microscopically in 100 mg/m3 males and females. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to particulate aerosols of indium phosphide with a mass median aerodynamic diameter of approximately 1.2 microm at concentrations of 0, 1, 3, 10, 30, or 100 mg/m3 by inhalation, 6 hours per day, 5 days per week (weeks 1 through 4 and weeks 10 through 14)or 7 days per week (weeks 5 through 9). Although the effects of indium phosphide exposure were similar in rats and mice, mice were more severely affected in that all males and females in the 100 mg/m3 groups either died or were removed moribund during the study. One male and three females in the 30 mg/m3 group were also removed before the end of the study. In general, body weight gains were significantly less in males and females exposed to 3 mg/m3 or greater compared to those of the chamber controls. Mice exposed to 30 or 100 mg/m3 were lethargic and experienced rapid, shallow breathing. As in rats, lungs were discolored and enlarged 2.6- to 4.1-fold greater than those of chamber controls due to the exposure-induced alveolar proteinosis. Indium phosphide particles were observed in the nose, trachea,larynx, and lymph nodes of some exposed males and females. Alveolar proteinosis, chronic active inflammation,interstitial fibrosis, and alveolar epithelial hyperplasia were observed; these effects were more severe than in rats. Hyperplasia in the bronchial lymph nodes and squamous metaplasia, necrosis, and suppurative inflammation of the larynx were observed in some exposed males and females. Exposure to indium phosphide induced a microcytic erythrocytosis which was consistent with the observed hematopoietic cell proliferation of the spleen.2-YEAR STUDY IN RATS Groups of 60 male and 60 female rats were exposed to particulate aerosols of indium phosphide at concentrations of 0, 0.03, 0.1, or 0.3 mg/m3, 6 hours per day,5 days per week, for 22 weeks (0.1 and 0.3 mg/m3 groups) or 105 weeks (0 and 0.03 mg/m3 groups). Animals in the 0.1 and 0.3 mg/m3 group were maintained on filtered air from exposure termination at week 22 until the end of the studies. Ten males and 10 females per group were evaluated at 3 months. 3-Month Interim Evaluation: Exposure to indium phosphide for 3 months caused a microcytic erythrocytosis and also caused enlarged lungs and lesions in the respiratory tract and lung associated lymph nodes. Although qualitatively similar to those observed in the 14-week studies, these effects were considerably less severe. However, the lesions in the lungs of rats exposed to 0.1 or 0.3 mg/m3 were considered sufficiently severe that exposure was discontinued in these groups, and the groups were allowed to continue unexposed for the remainder of the study. Survival, Body Weights, and Clinical Findings: Exposure to indium phosphide had no effect on survival or body weight gain. During the last 6 months of the study, rats in the 0.03 and 0.3 mg/m3 groups became lethargic and males breathed abnormally. Pathology Findings: At 2 years, exposure to indium phosphide caused increased incidences of alveolar/bronchiolar adenomas and carcinomas in rats. Squamous cell carcinoma of the lung occurred in four male rats exposed to 0.3 mg/m3. As observed in the 14-week study and at the 3-month interim evaluation, a spectrum of inflammatory and proliferative lesions of the lung were observed in all exposed groups of males and females;however, the extent and severity of the lesions were generally greater and included atypical hyperplasia,chronic inflammation, alveolar epithelial hyperplasia and metaplasia, alveolar proteinosis, and interstitial fibrosis. Exposure to indium phosphide also caused increased incidences of benign and malignant pheochromocytomas of the adrenal gland in males and females. Marginal increases in the incidences of mononuclear cell leukemia in males and females, fibroma of the skin in males, and carcinoma of the mammary gland in females may have been related to exposure to indium phosphide. 2-YEAR STUDY IN MICE: Groups of 60 male and 60 female mice were exposed to particulate aerosols of indium phosphide at concentrations of 0, 0.03, 0.1, or 0.3 mg/m3, 6 hours per day,5 days per week, for 21 weeks (0.1 and 0.3 mg/m3 groups) or 105 weeks (0 and 0.03 mg/m3 groups). Animals in the 0.1 and 0.3 mg/m3 groups were maintained on filtered air from exposure termination at week 21 until the end of the studies. Ten males and 10 females per group were evaluated at 3 months. 3-Month Interim Evaluation:Exposure to indium phosphide for 3 months affected the circulating erythroid mass and caused enlarged lungs and lesions in the respiratory tract and lung associated lymph nodes. These effects, although qualitatively similar to those observed in the 14-week studies, were considerably less severe. However, the lesions in the lungs of mice exposed to 0.1 mg/m3 and greater were considered sufficiently severe that exposure was discontinued in these groups and the groups were allowed to continue unexposed for the remainder of the study. Survival and Body Weights: In general, exposure to indium phosphide for 2 years reduced survival and body weight gain in exposed males and females. Pathology Findings:At 2 years, exposure to indium phosphide caused increased incidences of alveolar/bronchiolar carcinomas in males and alveolar/bronchiolar adenomas and carcinomas in females. In addition to the alveolar proteinosis and chronic active inflammation seen at earlier time points, serosa fibrosis and pleural mesothelial hyperplasia were also present. The incidences of hepatocellular neoplasms were also significantly increased in exposed males and females. Exposed groups of males and females had increased incidences of eosinophilic foci of the liver at 2 years. Marginal increases in the incidences of neoplasms of the small intestines in male mice may have been related to exposure to indium phosphide. Exposure to indium phosphide also caused inflammation of the arteries of the heart, primarily the coronary arteries and the proximal aorta, and to a lesser extent the lung-associated lymph nodes in males and in females. TISSUE BURDEN ANALYSES: Deposition and clearance studies of indium following long term exposure of rats and mice to indium phosphide by inhalation were performed. Although there were quantitative differences in lung burden and kinetic parameters for rats and mice, qualitatively they were similar. Deposition of indium in the lungs appeared to follow a zero-order (constant rate) process. Retained lung burdens throughout the studies were proportional to exposure concentration and duration. No differences in elimination rates of indium from the lungs were observed as a function of exposure concentration in either rats or mice. These studies indicated that elimination of indium was quite slow. Mice exhibited clearance half-times of 144 and 163 days for the 0.1 and 0.3 mg/m3 groups, respectively, as compared to 262 and 291 days for rats exposed to the same concentrations. The lung deposition and clearance model was used to estimate the total amount of indium deposited in the lungs of rats and mice after exposure to 0.03 mg/m3 for 2 years or to 0.1 or 0.3 mg/m3 for 21 or 22 weeks, the lung burdens at the end of the 2-year study, and the area under lung burden curves (AUC). For both species, estimates at the end of 2 years indicated that the lung burdens in the continuously exposed 0.03 mg/m3 groups were greater than those in the 0.1 or 0.3 mg/m3 groups. (ABSTRACT TRUNCATED)
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PMID:Toxicology and carcinogenesis studies of indium phosphide (CAS No. 22398-90-7) in F344/N rats and B6C3F1 mice (inhalation studies). 1208 22

2,2-Bis(bromomethyl)-1,3-propanediol is used as a fire retardant in unsaturated polyester resins, in molded products, and in rigid polyurethane foam. 2,2-Bis(bromomethyl)-1,3-propanediol was chosen for study because it is a widely used flame retardant and little toxicity and carcinogenicity data were available. Groups of male and female F344/N rats and B6C3F1 mice were exposed to technical grade 2,2-bis(bromomethyl)-1,3-propanediol (78.6% pure) in feed for 13 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, mouse bone marrow, and mouse peripheral blood. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were fed diets containing 0, 1,250, 2,500, 5,000, 10,000, or 20,000 ppm 2,2-bis(bromomethyl)- 1,3-propanediol for 13 weeks. These levels corresponded to approximately 100, 200, 400, 800, or 1,700 mg 2,2-bis(bromomethyl)-1,3-propanediol/kg body weight (males) and 100, 200, 400, 800, or 1,600 mg/kg (females). No rats died during the studies. The final mean body weights and weight gains of 5,000, 10,000, and 20,000 ppm males and females were significantly lower than those of the controls. Feed consumption by exposed animals was lower than that by controls at week 1, but was generally similar to or slightly higher than that by controls at week 13. No chemical-related clinical findings were observed. Chemical-related differences in clinical pathology parameters included increased urine volumes accompanied by decreased urine specific gravity and minimally increased protein excretion in 10,000 and 20,000 ppm males. In females, urine parameters were less affected than males. Water deprivation tests demonstrated that male and female rats were able to adequately concentrate their urine in response to decreased water intake. Serum protein and albumin concentrations in female rats exposed to 2,500 ppm and higher were slightly lower than those of the controls. Renal papillary degeneration was present in 5,000 and 10,000 ppm males, and in 20,000 ppm males and females. Hyperplasia of the urinary bladder was present in 20,000 ppm males. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were fed diets containing 0, 625, 1,250, 2,500, 5,000, or 10,000 ppm 2,2-bis(bromomethyl)-1,3-propanediol for 13 weeks. These levels corresponded to approximately 100, 200, 500, 1,300, or 3,000 mg 2,2-bis(bromomethyl)-1,3-propanediol/kg body weight (males) and 140, 300, 600, 1,200, or 2,900 mg/kg (females). One control female, two males and one female receiving 625 ppm, one female receiving 1,250 ppm, one female receiving 2,500 ppm, one female receiving 5,000 ppm, and three males receiving 10,000 ppm died during the study. The final mean body weights and body weight gains of males and females receiving 1,250, 2,500, 5,000, or 10,000 ppm and of females receiving 625 ppm were significantly lower than those of the controls. Feed consumption by exposed mice was generally higher than that by controls throughout the study. Clinical findings included abnormal posture and hypoactivity in 10,000 ppm male and female mice. Blood urea nitrogen concentrations of 5,000 ppm females and 10,000 ppm males and females were greater than those of controls. Also, urine specific gravity was lower in 10,000 ppm females. Differences in organ weights generally followed those in body weights. Papillary necrosis, renal tubule regeneration, and fibrosis were observed in the kidneys of 2,500 and 5,000 ppm males and 10,000 ppm males and females. Urinary bladder hyperplasia was observed in 5,000 and 10,000 ppm males and females. 2-YEAR STUDY IN RATS: Groups of 60 male and 60 female rats received 2,500, 5,000, or 10,000 ppm 2,2-bis(bromomethyl)- 1,3-propanediol in feed for 104 to 105 weeks. Groups of 70 males and 60 females received 0 ppm 2,2-bis(bromomethyl)-1,3-propanediol in feed for 104 to 105 weeks. A stop-exposure group of 70 male rats received 20,000 ppm 2,2-bis(bromomethyl)-1,3-propanediol in feed for 3 months, after which animals received undosed feed for the remainder of the 2-year styear study. Average daily doses of 2,2-bis(bromomethyl)-1,3-propanediol were 100, 200, or 430 mg/kg body weight for males and 115, 230, or 460 mg/kg for females. Stop-exposure males received an average daily dose of 800 mg/kg. Ten animals from the 0 ppm male group and the 20,000 ppm stop-exposure group were evaluated at 3 months; nine or 10 control animals and five to nine animals from each of the continuous-exposure groups were evaluated at 15 months. Survival, Body Weights, Feed Consumption, and Clinical Findings: Survival of 5,000 and 10,000 ppm continuous-exposure study males and females and 20,000 ppm stop-exposure males was significantly lower than that of the controls. Mean body weights of exposed male and female rats receiving 10,000 ppm and stop-exposure males receiving 20,000 ppm were lower than those of the controls throughout most of the study. In the continuous-exposure study, feed consumption by exposed rats was generally similar to that by controls throughout the study. In 20,000 ppm stop-exposure males, the feed consumption was lower than that by controls. Clinical findings included skin and/or subcutaneous masses on the face, tail, and the ventral and dorsal surfaces of exposed rats. Pathology Findings: In the 2-year continuous and stop-exposure studies in male rats, exposure to 2,2-bis(bromomethyl)-1,3-propanediol was associated with neoplastic effects in the skin, mammary gland, Zymbal's gland, oral cavity, esophagus, forestomach, small and large intestines, mesothelium, urinary bladder, lung, thyroid gland, hematopoietic system, and seminal vesicle. Nonneoplastic effects in the kidney, lung, thyroid gland, seminal vesicle, pancreas, urinary bladder, and forestomach were also observed. In females, 2-year exposure to 2,2-bis(bromomethyl)-1,3-propanediol was associated with neoplastic effects in the oral cavity, esophagus, mammary gland, and thyroid gland. Nonneoplastic effects in the kidney were also observed. These findings are outlined in the two summary tables. 2-YEAR STUDY IN MICE: Groups of 60 male and 60 female mice received 0, 312, 625, or 1,250 ppm 2,2-bis(bromomethyl)-1,3-propanediol in feed for 104 to 105 weeks. Average daily doses of 2,2-bis(bromomethyl)-1,3-propanediol were 35, 70, or 140 mg/kg (males) and 40, 80, or 170 mg/kg (females). Eight to 10 animals from each group were evaluated at 15 months. Survival, Body Weights, Feed Consumption, and Clinical Findings: Survival of 1,250 ppm males and females was significantly lower than that of the controls. Mean body weights of exposed male and female mice were similar to controls throughout the study. Final mean body weights were also generally similar to those of controls. Feed consumption by exposed male and female mice was similar to that by controls. Clinical findings included tissue masses involving the eye in exposed mice. Pathology Findings: Exposure of male mice to 2,2-bis(bromomethyl)-1,3-propanediol for 2 years was associated with neoplastic effects in the harderian gland, lung, and kidney. Exposure of female mice to 2,2-bis(bromomethyl)-1,3-propanediol was associated with increased incidences of neoplasms of the harderian gland, lung, and skin. Nonneoplastic effects in the lung were also observed in exposed females. These findings are outlined in the two summary tables. GENETIC TOXICOLOGY: 2,2-Bis(bromomethyl)-1,3-propanediol was mutagenic in Salmonella typhimurium strain TA100 when tested in the presence of induced 30% hamster liver S9; all other strain/activation combinations gave negative results. In cultured Chinese hamster ovary cells, 2,2-bis(bromomethyl)-1,3-propanediol induced chromosomal aberrations only in the presence of S9; no induction of sister chromatid exchanges was observed in cultured Chinese hamster ovary cells after treatment with 2,2-bis(bromomethyl)-1,3-propanediol, with or without S9. In vivo, 2,2-bis(bromomethyl)-1,3-propanediol induced significant increases in the frequencies of micronucleated erythrocytes in male and female mice. Significant increases in micronuclei were observed in peripheral blood samples from male and female mice exposed to 2,2-bis(bromomethyl)-1,3-propanediol for 13 weeks via dosed feed. Results of a bone marrow micronucleus test in male mice, where 2,2-bis(bromomethyl)-1,3-propanediol was administered by gavage, were considered to be equivocal due to inconsistent results obtained in two trials. An additional bone marrow micronucleus test was performed with male and female mice and 2,2-bis(bromomethyl)-1,3-propanediol was administered as a single intraperitoneal injection; results of this test were positive in females and negative in males. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was clear evidence of carcinogenic activity of 2,2-bis-(bromomethyl)-1,3-propanediol (FR-1138) in male F344/N rats based on increased incidences of neoplasms of the skin, subcutaneous tissue, mammary gland, Zymbal's gland, oral cavity, esophagus, forestomach, small and large intestines, mesothelium, urinary bladder, lung, thyroid gland, and seminal vesicle, and the increased incidence of mononuclear cell leukemia. There was clear evidence of carcinogenic activity of 2,2-bis(bromomethyl)-1,3-propanediol in female F344/N rats based on increased incidences of neoplasms of the oral cavity, esophagus, mammary gland, and thyroid gland. There was clear evidence of carcinogenic activity of 2,2-bis(bromomethyl)-1,3-propanediol in male B6C3F1 mice based on increased incidences of neoplasms of the harderian gland, lung, and kidney. There was clear evidence of carcinogenic activity of 2,2-bis(bromomethyl)-1,3-propanediol in female B6C3F1 mice based on increased incidences of neoplasms of the harderian gland, lung, and subcutaneous tissue. Slight increases in the incidences of neoplasms of the pancreas and kidney in male rats; forestomach in male mice; and forestomach, mammary gland, and circulatory system in female mice may have also been related to treatment. Exposure of male and female rats to 2,2-bis(bromomethyl)-1,3-propanediol was associated with alveolar/bronchiolar hyperplasia in the lung (males only); focal atrophy, papillary degeneration, transitional epithelial hyperplasia (pelvis), and papillary epithelial hyperplasia in the kidney; follicular cell hyperplasia in the thyroid gland (males only); hyperplasia in the seminal vesicle and pancreas (males only); mucosal hyperplasia in the forestomach (males only); and urinary bladder hyperplasia (males only). Exposure of mice to 2,2-bis(bromomethyl)-1,3-propanediol was associated with hyperplasia of the alveolar epithelium in females. Synonyms: 2,2-Bis(2-bromomethyl)-1,3-propanediol; 1,3-dibromo-2,2-dihydroxymethylpropane; 1,3-dibromo-2,2-dimethylolpropane; 2,2-dibromomethyl-1,3-propanediol; dibromopentaerythritol; dibromoneopentyl glycol; pentaerythritol dibromide; pentaerythritol dibromohydrin
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PMID:NTP Toxicology and Carcinogenesis Studies of 2,2-Bis(Bromomethyl)-1,3-Propanediol (FR-1138(R)) (CAS No. 3296-90-0) in F344 Rats and B6C3F1 Mice (Feed Studies). 1259 23

Isobutyl nitrite is used to a limited extent as an intermediate in the syntheses of aliphatic nitrites. It is also an ingredient of various incenses or room odorizers and is used as a euphoric. The chemical has also been used as a jet propellant and in the preparation of fuels. Isobutyl nitrite was nominated by the Consumer Product Safety Commission to the NTP for toxicology and carcinogenicity studies because of its possible contribution to the high incidence of Kaposi's sarcoma among male homosexual acquired immune deficiency syndrome patients and because of the lack of available data on the potential carcinogenicity of isobutyl nitrite. Male and female F344/N rats and B6C3F1 mice were exposed to isobutyl nitrite (purity of 93% or greater) by inhalation for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, Drosophila melanogaster, and mouse peripheral blood. 16-DAY STUDY IN RATS: Groups of five male and five female F344/N rats were exposed to 0, 100, 200, 400, 600, or 800 ppm (approximately 420, 840, 1,700, 2,500, or 3,300 mg/m(3)) isobutyl nitrite by inhalation for 6 hours per day, 5 days per week for a total of 12 exposures during a 16-day period. All males and females exposed to 600 or 800 ppm and one 400 ppm female died on the first day of the study. Final mean body weights and mean body weight gains of 400 ppm males and females were significantly lower than those of the controls. Clinical findings observed in 400 ppm males and females included ocular discharge, lethargy, hunched posture, and rough coats. Absolute and relative lung weights of all exposed groups of males and of 200 and 400 ppm females were less than those of the controls. Chemical-related hyperplasia of the bronchial epithelium was observed in 200 and 400 ppm males and females and hyperplasia of the nasal turbinate epithelium was observed in rats exposed to 400 ppm or less. Hemosiderin pigmentation was observed in the spleen of 200 and 400 ppm males and females and bone marrow hematopoietic hyperplasia was observed in rats exposed to 400 ppm or less. 16-DAY STUDY IN MICE: Groups of five male and five female B6C3F1 mice were exposed to 0, 100, 200, 400, 600, or 800 ppm (approximately 420, 840, 1,700, 2,500, or 3,300 mg/m(3)) isobutyl nitrite by inhalation for 6 hours per day, 5 days per week for a total of 12 exposures during a 16-day period. Three males and four females exposed to 800 ppm died before the end of the study. Final mean body weights and mean body weight gains of 600 and 800 ppm males and females were significantly lower than those of the controls. Mice exposed to 400 ppm or greater were lethargic and exhibited hunched posture and rough coats. Absolute and relative lung weights of 600 and 800 ppm males and the relative lung weight of 600 ppm females were significantly greater than those of the controls. Chemical-related hyperplasia of the bronchiolar epithelium was observed in all exposed groups of males and females. Lymphocytic atrophy of the spleen and thymus was observed in males and females exposed to 400 ppm or greater. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were exposed to 0, 10, 25, 75, 150, or 300 ppm (approximately 42, 105, 315, 630, or 1,260 mg/m(3)) isobutyl nitrite by inhalation for 6 hours per day, 5 days per week for 13 weeks. All rats survived to the end of the study. Final mean body weights and mean body weight gains of 300 ppm males and females were significantly lower than those of the controls, as was the mean body weight gain of 150 ppm females. Clinical findings observed during the study included ruffled fur in 300 ppm males and females, hypoactivity in 300 ppm males, and hyperactivity in 150 and 300 ppm females. A very mild chemical-related methemoglobinemia and anemia occurred in male and female rats in the 75, 150, and 300 ppm groups. Hematopoietic hyperplasia occurred in the bone marrow of all exposed groups of males and females and was considered to be a secondary response to the anemia and methed methemoglobinemia. There was minimal hemosiderin pigment accumulation in the spleens of males and females exposed to 75 ppm or greater, mild to moderate epithelial cell hyperplasia of the nasal mucosa was observed in 300 ppm males and females, and minimal hyperplasia occurred in 150 ppm males and females. Hyperplasia of the bronchial epithelium was observed in 300 ppm males and females. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were exposed to 0, 10, 25, 75, 150, or 300 ppm (approximately 42, 105, 315, 630, or 1,260 mg/m(3)) isobutyl nitrite by inhalation for 6 hours per day, 5 days per week for 13 weeks. There were no chemical-related deaths. Final mean body weights and mean body weight gains of 150 and 300 ppm females were significantly less than those of the controls. Final mean body weights and mean body weight gains of exposed groups of males were similar to those of the controls. There were no chemical-related clinical findings. A very mild chemical-related methemoglobinemia occurred in male and female mice in the 150 and 300 ppm groups. A very mild anemia occurred in the 300 ppm groups. In the lung, increased incidences of mild to moderate hyperplasia of the bronchiolar epithelium occurred in males and females exposed to 300 ppm. Minimal hyperplasia occurred in males exposed to 75 ppm or greater and in females exposed to 150 ppm. Minimal epithelial cell hyperplasia of the nasal mucosa was observed in 300 ppm males. Increased hematopoiesis of the spleen, secondary to the hematotoxicity, occurred in males exposed to 75 ppm or greater and in females exposed to 150 or 300 ppm. Increased hemosiderosis of the spleen occurred in males exposed to 300 ppm and in females exposed to 75 ppm or greater. 2-YEAR STUDY IN RATS: Based on the low final mean body weights, anemia, and the mild to moderate nasal mucosal lesions and the hyperplastic bronchial lesions observed in 300 ppm males and females, isobutyl nitrite exposure concentrations selected for the 2-year inhalation study in rats were 37.5, 75, and 150 ppm. Groups of 56 male and 56 female rats were exposed to 0, 37.5, 75, or 150 ppm (equivalent to 0, 158, 315, or 630 mg/m(3)) isobutyl nitrite by inhalation for 6 hours per day, 5 days per week, for 103 weeks. Ten male and 10 female rats from each group were evaluated at 15 months for clinical pathology and histopathology. Survival, Body Weights, Clinical Findings, Hematology, and Clinical Chemistry: Survival rates of exposed groups of rats were greater than those of the controls, and the survival rates of 75 and 150 ppm males were significantly greater than that of the control. Mean body weights of 150 ppm males and females were 3% to 11% lower than those of the controls throughout the course of the study. There were no clinical findings considered to be related to isobutyl nitrite exposure. A very mild methemoglobinemia and anemia occurred in male and female rats exposed to 75 or 150 ppm. Pathology Findings: Incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar adenoma or carcinoma (combined) occurred with significant positive trends in exposed males and females, and the incidences of these neoplasms in 75 ppm males and in 150 ppm males and females were significantly greater than those in the controls. The incidence of alveolar/bronchiolar carcinoma was significantly greater in 150 ppm male rats than that in the controls. The incidences of alveolar epithelial hyperplasia were also increased in 75 and 150 ppm males and in all exposed groups of females. The incidences of mononuclear cell leukemia in exposed groups of males and females were significantly less than those in the controls. 2-YEAR STUDY IN MICE: Based on the low final mean body weight of 300 ppm females and the mild to moderate bronchiolar hyperplasia observed in 300 ppm males and females, isobutyl nitrite exposure concentrations selected for the 2-year inhalation study in mice were 37.5, 75, and 150 ppm. Groups of 60 male and 60 female mice were exposed to 0, 37.5, 75, or 150 ppm (equivalent to 0, 158, 315, or 630 mg/m(3)) isobutyl nitrite by inhalation for 6 hours per day, 5 days per week, for 103 weeks. As many as 10 male and 10 female mice from each group were evaluated at 15 months for clinical pathology and histopathology. Survival, Body Weights, Clinical Findings, and Hematology and Clinical Chemistry: Survival rates of exposed groups of males were similar to those of the controls. Survival rates of exposed groups of females were greater than those of the controls, and the survival rate in 37.5 ppm females was significantly greater than that of the controls. Mean body weights of exposed groups of males and of 37.5 and 75 ppm females were similar to those of the controls throughout the study. Mean body weights of 150 ppm females were lower than those of the controls from week 20 until the end of the study. There were no biologically significant clinical findings noted in the 2-year study in mice. A very mild methemoglobinemia and anemia occurred in male and female mice exposed to 75 or 150 ppm. Pathology Findings: Incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar adenoma or carcinoma (combined) occurred with significant positive trends in exposed males and females, and the incidences of these neoplasms were significantly greater than those in the controls in 75 ppm males and in 150 ppm males and females. Incidences of alveolar epithelial hyperplasia were significantly increased in 75 and 150 ppm male and female mice. Thyroid gland follicular cell adenoma occurred with a significant positive trend in male mice; the incidences of thyroid gland follicular cell hyperplasia were increased in all exposed groups of males, and the incidences in males exposed to 37.5 or 150 ppm were significantly greater than those in the controls. Incidences of serous exudate and olfactory epithelium atrophy in the nose of 150 ppm females were significantly greater than those in the controls. Incidences of minimal to mild hemosiderin pigment in the spleen of 75 and 150 ppm male mice were significantly greater than those in the controls. GENETIC TOXICOLOGY: Isobutyl nitrite was found to be mutagenic in vitro and in vivo. It induced base-pair substitution mutations in Salmonella typhimurim strains TA100 and TA1535 and sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells. Positive responses in the S. typhimurium tests required S9 activation, but isobutyl nitrite induced chromosomal effects in cultured Chinese hamster ovary cells with and without S9. In vivo, no induction of sex-linked recessive lethal mutations was noted in the germ cells of male Drosophila melanogaster exposed to isobutyl nitrite via feeding or injection. However, significant increases in micronucleated normochromatic erythrocytes were observed in the peripheral blood of male and female mice treated with isobutyl nitrite for 90 days by inhalation. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was clear evidence of carcinogenic activity of isobutyl nitrite in male and female F344/N rats based on the increased incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar adenoma or carcinoma (combined). There was some evidence of carcinogenic activity of isobutyl nitrite in male and female B6C3F1 mice based on the increased incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar adenoma or carcinoma (combined) in males and females. The increased incidence of thyroid gland follicular cell adenoma in male mice may have been related to isobutyl nitrite exposure. Exposure of rats and mice to isobutyl nitrite by inhalation for 2 years resulted in increased incidences of alveolar epithelial hyperplasia (male and female rats and mice), thyroid gland follicular cell hyperplasia and splenic hemosiderin pigmentation (male mice), and serous exudate and atrophy of the olfactory epithelium of the nose (female mice). Exposure of rats to isobutyl nitrite by inhalation for 2 years resulted in decreased incidences of mononuclear cell leukemia in males and females.
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PMID:NTP Toxicology and Carcinogenesis Studies of Isobutyl Nitrite (CAS No. 542-56-3) in F344 Rats and B6C3F1 Mice (Inhalation Studies). 1259 27

o-Nitroanisole is used as an intermediate for the preparation of o-anisidine and in the manufacture of azo dyes. Toxicology and carcinogenesis studies were conducted by administering o-nitroanisole (>99% pure) in the diet to groups of male and female F344 rats and B6C3F1 mice for 14 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Chinese hamster ovary cells, and mouse lymphoma cells. 14-DAY STUDIES: Groups of five male and five female F344 rats received diets containing 0, 583, 1,166, 2,332, 4,665, or 9,330 ppm o-nitroanisole. Mean body weight gains and final mean body weights of males in the 4,665 and 9,330 ppm groups were lower than those of the controls. Absolute liver weights were significantly increased in males receiving 1,166 ppm or more and in females receiving 583 ppm or more. Groups of five male and five female B6C3F1 mice received diets containing 0, 250, 500, 1,000, 2,000, or 4,000 ppm o-nitroanisole. Mean body weight gains and final mean body weights of males that received 250 ppm and females that received 4,000 ppm were significantly lower than those of the controls. No other chemical-associated effects were observed. 13-WEEK STUDIES: Groups of 10 male and 10 female F344 rats received diets containing 0, 200, 600, 2,000, 6,000, or 18,000 ppm o-nitroanisole. Final mean body weights and feed consumption by male and female rats receiving 6,000 and 18,000 ppm were lower than those of the controls. Hemoglobin and hematocrit values were significantly lower and methemoglobin levels significantly higher in males in the 6,000 and 18,000 ppm groups than in controls. Absolute liver weights were significantly increased in females that received 200, 600, 2,000, and 6,000 ppm, absolute kidney weights were significantly increased in males that received 600, 2,000, and 6,000 ppm, and absolute spleen weights were significantly increased in males and females that received 6,000 and 18,000 ppm. Groups of 10 male and 10 female B6C3F1 mice received diets containing 0, 60, 200, 600, 2,000, or 6,000 ppm o-nitroanisole. Final mean body weight gains, final mean body weights, and feed consumption by male and female mice receiving 6,000 ppm were lower than those of the controls. Hemoglobin and hematocrit values in males and females that received 2,000 or 6,000 ppm were significantly lower than those in the controls. The absolute and relative liver weights of females in the 600 ppm group and relative liver weights of males and females in the 2,000 and 6,000 ppm groups were significantly greater than those of controls. Lesions associated with exposure to o-nitroanisole were present in the urinary bladder, spleen, kidney, liver, testis, and uterus of rats. Diffuse hyperplasia of the transitional epithelium of the urinary bladder occurred in all male and female rats that received 6,000 and 18,000 ppm. A transitional cell papilloma occurred in one male and transitional cell carcinomas occurred in two males and three females receiving 18,000 ppm. Congestion of the red pulp and capsular hyperplasia of the spleen and hepatocellular hypertrophy of the liver were present in males and females from the 18,000 ppm groups. Multifocal degeneration and necrosis of the renal tubule epithelium with infiltration of mononuclear inflammatory cells were present in male rats that received 600, 2,000, and 6,000 ppm. At the 18,000 ppm level, degeneration of the seminiferous epithelium accompanied by loss of spermatogenic cells and decreased numbers of spermatozoa were observed in the testes of male rats, while uterine atrophy was observed in female rats. Hepatocyte hypertrophy of the centrilobular and midzonal regions of liver lobules was present in mice that received 200 ppm and increased in severity at higher exposure levels. 2-YEAR STUDIES: The doses selected for the 2-year study of o-nitroanisole in rats were based on lower mean body weights, reduced feed consumption, and increased severity of regenerative anemia in male and female rats receiving 6,000 and 18,000 ppm during the 13-week study. Groups of 6roups of 60 male and 60 female F344 rats received diets containing 0, 222, 666, or 2,000 ppm o-nitroanisole. Groups of 60 male and 60 female B6C3F1 mice received diets containing 0, 666, 2,000, or 6,000 ppm o-nitroanisole. After 15 months, up to 10 animals from each group were evaluated for chemical-related lesions. Survival, Body Weights, Feed Consumption, and Clinical Findings: Survival of male rats receiving 2,000 ppm was significantly lower than that of the controls due to increased severity of nephropathy. Survival of 222 and 666 ppm male rats and all exposed female rats was similar to that of the controls. Survival of groups of exposed male and female mice was similar to that of the controls. The final mean body weight of male rats receiving 2,000 ppm was lower than that of the controls. Final mean body weights of male and female mice that received 2,000 and 6,000 ppm were lower than those of the controls. Feed consumption by male and female rats was similar to that by the controls. The only clinical finding in male or female mice attributable to chemical administration was discolored urine. Neoplasms and Nonneoplastic Lesions: The incidence of mononuclear cell leukemia was significantly increased in male rats that received 666 and 2,000 ppm and in female rats that received 2,000 ppm (males: 0 ppm, 26/50; 222 ppm, 25/50; 666 ppm, 42/50; 2,000 ppm, 34/50; females: 14/50, 11/50, 14/50, 26/50). Nephropathy occurred in all male rats; the severity increased with exposure level. Focal hyperplasia of the renal tubule epithelium was present in three males receiving 222 ppm and two males receiving 2,000 ppm. Renal tubule adenomas occurred in one male from each of the 222, 666, and 2,000 ppm groups, and renal tubule carcinomas occurred in two males from the 2,000 ppm group. Focal hyperplasia of the transitional epithelium of the urinary bladder was present in one female rat that received 222 ppm and two male rats and six female rats that received 2,000 ppm. A transitional cell papilloma occurred in the urinary bladder of one female rat from the 2,000 ppm group, and a transitional cell carcinoma occurred in another female from the 2,000 ppm group. The incidence of forestomach ulcers increased in male rats that received 2,000 ppm, and the incidence of focal hyperplasia of the forestomach increased with exposure level in male and female rats. In addition, squamous cell papillomas of the forestomach were present in one female receiving 222 ppm, one male receiving 666 ppm, and one male and one female receiving 2,000 ppm, while squamous cell carcinomas were present in one male receiving 666 ppm and one male and one female receiving 2,000 ppm. The incidences of pituitary gland adenomas in male rats and mammary gland fibroadenomas in female rats decreased with exposure level. The incidence of cellular alteration in the liver was significantly increased in exposed groups of male and female mice. The incidences of hepatocellular adenoma, hepatocellular adenoma or carcinoma (combined), and hepatocellular carcinoma or hepatoblastoma (combined) were significantly increased in male mice receiving 2,000 and 6,000 ppm. The incidences of hepatocellular adenoma or carcinoma were significantly increased in female mice that received 2,000 ppm. STOP-EXPOSURE STUDY: Groups of 60 male and 60 female F344 rats received diets containing 0, 6,000, or 18,000 ppm o-nitroanisole for 27 weeks and were then maintained on control feed without further chemical exposure for up to an additional 77 weeks. Up to 10 rats from each group were evaluated for the presence of chemical-related lesions at 3, 6, 9, and 15 months. Survival and Body Weights: Survival of exposed male and female rats was significantly lower than that of the controls as a result of moribund deaths associated with significantly increased incidences of urinary bladder neoplasms, primarily transitional cell carcinomas. All male rats that received 18,000 ppm were dead by week 48 and all females that received 18,000 ppm were dead by week 61. Mean body weights of exposed male and female rats were lower than those of the controls throughout the study. Neoplasms and Nonneoplastic Lesions: Hyperplasia of the transitional epithelium of the urinary bladder was present in nearly all exposed male and female rats examined at the interim evaluations. A transitional cell carcinoma was first observed at the 3-month interim evaluation in a male rat that received 18,000 ppm. At the 6- and 9-month interim evaluations, transitional cell papillomas or carcinomas were observed in both exposed groups of male rats. Transitional cell carcinomas were observed at the 6-month interim evaluation in females receiving 18,000 ppm and at the 9-month interim evaluation in females receiving 6,000 and 18,000 ppm. Adenomatous polyps of the large intestine were observed in a small number of exposed rats at the 6-, 9-, and 15-month interim evaluations. At the end of the study, the incidence of adenomatous polyps of the large intestine was significantly increased in all exposed groups and carcinomas of the large intestine were present in four males and two females from the 18,000 ppm groups. The incidence of hyperplasia of the transitional epithelium of the kidney pelvis was significantly increased in exposed male and female rats and transitional cell papillomas were present in three males and one female that received 18,000 ppm. Transitional cell carcinomas of the kidney were present in one male receiving 6,000 ppm and six males and one female receiving 18,000 ppm. Transitional cell carcinomas of the urinary bladder were seen in nearly all exposed male and female rats. Of the males and females receiving 6,000 ppm which were without carcinomas, three males and one female had transitional cell papillomas. Generalized centrilobular hypertrophy, focal hepatocellular necrosis, multifocal hepatocellular cytoplasmic vacuolation, and Kupffer cell pigmentation were observed in the livers of male and female rats at the 3- and 6-month interim evaluations; however, only Kupffer cell pigmentation was observed at the end of the study. Congestion of the red pulp of the spleen was observed in nearly all exposed male and female rats at the 3-, 6-, and 9-month interim evaluations but the incidence was only slightly increased in the 18,000 ppm groups at the end of the study. Degeneration and atrophy of the seminiferous tubule epithelium of the testes were observed at the 3- and 6-month interim evaluations in all male rats receiving 18,000 ppm. GENETIC TOXICOLOGY: o-Nitroanisole was tested in two laboratories for mutagenicity in Salmonella typhimurium strains TA97, TA98, TA100, TA1535, and TA1537 with and without exogenous metabolic activation (S9). Positive responses were observed at both laboratories in TA100 with and without S9 activation. One laboratory found no increase in mutations, while the second laboratory detected a weakly positive response in TA1535 without S9. No mutagenic activity was observed in the other tester strains. o-Nitroanisole was positive in the mouse lymphoma assay for induction of trifluorothymidine resistance in L5178Y cells without S9 activation. In cytogenetic tests with Chinese hamster ovary cells, o-nitroanisole induced a significant increase in chromosomal aberrations at the highest dose tested in the presence of S9 activation; sister chromatid exchanges were induced both with and without S9. CONCLUSIONS: Under the conditions of these feed studies there was clear evidence of carcinogenic activity of o-nitroanisole in male and female F344 rats that received diets containing 6,000 or 18,000 ppm for 6 months based on overall increased incidences of benign and malignant neoplasms of the urinary bladder, transitional cell neoplasms of the kidney, and benign and malignant neoplasms of the large intestine. There was a chemical-related increased incidence of mononuclear cell leukemia in male and female rats receiving diets containing 222, 666, or 2,000 ppm o-nitroanisole for 2 years. Marginally increased incidences of uncommon renal tubule neoplasms in male rats and forestomach neoplasms in male and female rats were considered uncertain findings. There was clear evidence of carcinogenic activity of o-nitroanisole in male B6C3F1 mice based on increased incidences of benign and malignant hepatocellular neoplasms. There was some evidence of carcinogenic activity of o-nitroanisole in female B6C3F1 mice based on increased incidences of hepatocellular adenomas. Increased severity of nephropathy in male rats, and increased incidences of focal hyperplasia of the renal tubule epithelium and forestomach ulcers in male rats, and of transitional cell hyperplasia of the urinary bladder, focal hyperplasia of the forestomach, and hyperplasia of transitional epithelium of the kidney pelvis in male and female rats were associated with exposure to o-nitroanisole. Synonyms: Methoxynitrobenzene, nitrophenyl methyl ether
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PMID:NTP Toxicology and Carcinogenesis Studies of o-Nitroanisole (CAS No. 91-23-6) in F344 Rats and B6C3F1 Mice (Feed Studies). 1261 95

Hydroquinone is used an antioxidant in the rubber industry and as a developing agent in photography. It is also an intermediate in the manufacture of rubber and food antioxidants and monomer inhibitors. Hydroquinone and products containing hydroquinone are used as depigmenting agents to lighten skin. NTP Toxicology and Carcinogenesis studies were conducted by administering hydroquinone (greater than 99% pure) in corn oil or water by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, or 2 years. Additionally, genetic toxicology studies were conducted in Salmonella typhimurium, mouse lymphoma cells, Chinese hamster ovary (CHO) cells, and Drosophila melanogaster. Preliminary 3-day dermal studies were conducted with rats and mice using sufficient hydroquinone in 95% ethanol to crystallize on the skin (4 or 40 mg per animal); conjugated metabolites of hydroquinone were detected in the urine. Fourteen-day dermal studies were conducted at doses up to 3,840 mg/kg for rats and 4,800 mg/kg for mice. No toxic effects were seen in the 3- or 14-day dermal studies. Therefore, in further evaluations of hydroquinone, the gavage route of administration was used. Results of Fourteen-Day and Thirteen-Week Studies: Fourteen-day gavage studies were conducted by administering hydroquinone in corn oil to rats at doses ranging from 63 to 1,000 mg/kg body weight and to mice at doses ranging from 31 to 500 mg/kg. All rats receiving 1,000 mg/kg and 1/5 male and 4/5 female rats receiving 500 mg/kg died before the end of the 14 days. Compound-related clinical signs in rats included tremors lasting up to 30 minutes after each dosing at 500 and 1,000 mg/kg. In the 14-day gavage studies with mice, 4/5 male mice and 5/5 female mice receiving 500 mg/kg and 3/5 males receiving 250 mg/kg died before the end of the studies. Tremors followed by convulsions were seen at 250 and 500 mg/kg. In the 13-week studies, doses for rats and mice ranged from 25 to 400 mg/kg. All rats receiving 400 mg/kg and 3/10 female rats receiving 200 mg/kg died before the end of the studies. The mean body weight at necropsy of male rats administered 100 or 200 mg/kg was about 8%-9% lower than that of vehicle controls. Mean body weights of vehicle control and dosed female rats at necropsy were similar. Tremors and convulsions were observed after dosing in most rats receiving 400 mg/kg and in several female rats receiving 200 mg/kg. Inflammation and/or epithelial hyperplasia (acanthosis) of the forestomach were seen in 4/10 male rats and 1/10 female rats receiving 200 mg/kg. Toxic nephropathy, characterized by tubular cell degeneration in the renal cortex, was seen in 7/10 male and 6/10 female rats receiving 200 mg/kg and in 1/10 females receiving 100 mg/kg. In the 13-week studies in mice, 8/10 males and 8/10 females receiving 400 mg/kg and 2/10 male mice receiving 200 mg/kg died early. Mean body weights of dosed and vehicle control mice at necropsy were similar. Liver weight to body weight ratios for dosed male mice were significantly greater than for vehicle controls. Ulceration, inflammation, or epithelial hyperplasia of the forestomach was found in 3/10 male and 2/10 female mice receiving 400 mg/kg and 1/10 females receiving 200 mg/kg. Based on these collective results, 2-year studies were conducted by administering 0, 25, or 50 mg/kg hydroquinone in deionized water by gavage to groups of 65 rats of each sex, 5 days per week. Groups of 65 mice of each sex were administered 0, 50, or 100 mg/kg on the same schedule. Ten rats and 10 mice from each group were killed after 15 months for an interim evaluation. Observations at Fifteen Months: In the rats killed at 15 months, the relative kidney weight for high dose male rats was greater than that for vehicle controls. The hematocrit value, hemoglobin concentration, and erythrocyte count for high dose female rats were decreased. Compound-related increased severity of nephropathy was observed in male rats. In mice killed at 15 months, the relative liver weights for high dose male and female mice were signif and female mice were significantly greater than those for vehicle controls. Lesions seen in the liver of male mice included increased syncytial cells and diffuse cytomegaly. Body Weights, Organ Weights, and Survival in the Two-Year Studies: Mean body weights of high dose male rats were 5%-13% lower than those of vehicle controls after week 73, and those of low dose male rats were 5%-9% lower than those of vehicle controls after week 89. Mean body weights of dosed female rats were similar to those of vehicle controls throughout the study. The relative kidney and liver weights for high dose male rats were higher than those for vehicle controls. Mean body weights of high dose male mice were 5%-8% lower than those of vehicle controls after week 93, and those of high dose female mice were 5%-14% lower after week 20. Relative liver weights were increased for dosed male and high dose female mice. No significant differences in survival were observed between any groups of rats or mice of either sex after 2 years (male rats: vehicle control, 27/55; low dose, 18/55; high dose, 18/55; female rats: 40/55; 27/55; 32/55; male mice: 33/55; 37/54; 36/55; female mice: 37/55; 39/55; 36/55). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Nearly all male rats and most female rats in all vehicle control and dosed groups had nephropathy. The severity of this disease was judged to be greater in high dose male rats. Hyperplasia of the renal pelvic transitional epithelium and renal cortical cysts, changes observed with advanced renal disease, were increased in male rats. Renal tubular hyperplasia was seen in 2 high dose male rats, and renal tubular adenomas were seen in 4/55 low dose and 8/55 high dose male rats; none was seen in vehicle controls. Mononuclear cell leukemia in female rats occurred with a positive trend, and the incidences in the dosed groups were greater than that in the vehicle controls (vehicle control, 9/55; low dose, 15/55; high dose, 22/55). The historical incidence of leukemia in water gavage vehicle control female F344/N rats is 25% ± 15% and in untreated controls is 19% ± 7%. Compound-related lesions observed in the liver of high dose male mice included anisokaryosis (0/55; 2/54; 12/55), syncytial alteration (5/55; 3/54; 25/55), and basophilic foci (2/55; 5/54; 11/55). The incidences of hepatocellular adenomas were increased in dosed male mice (9/55; 21/54; 20/55), but these increases were offset by decreases in the incidences of hepatocellular carcinomas (13/55; 11/54; 7/55). The incidences of hepatocellular neoplasms, primarily adenomas, were increased in dosed female mice (3/55; 16/55; 13/55). Follicular cell hyperplasia of the thyroid gland was increased in dosed mice (male: 5/55; 15/53; 19/54; female: 13/55; 47/55; 45/55). Follicular cell adenomas were seen in 2/55 vehicle control, 1/53 low dose, and 2/54 high dose male mice and in 3/55 vehicle control, 5/55 low dose, and 6/55 high dose female mice, a follicular cell carcinoma was seen in a seventh high dose female mouse. The highest observed incidence of follicular cell adenomas or carcinomas(combined) in historical water gavage vehicle control female B6C3F1 mice is 3/48 (6%). Genetic Toxicology: Hydroquinone was not mutagenic in S. typhimurium strains TA98, TA100, TA1535, or TA1537 with or without exogenous metabolic activation. It induced trifluorothymidine (Tft) resistance in mouse L5178Y/TK lymphoma cells in the presence or absence of metabolic activation. An equivocal response was obtained in tests for induction of sex-linked recessive lethal mutations in Drosophila administered hydroquinone by feeding. Hydroquinone induced sister chromatid exchanges (SCEs) in CHO cells both with or without exogenous metabolic activation and caused chromosomal aberrations in the presence of activation. Conclusions: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activity of hydroquinone for male F344/N rats, as shown by marked increases in tubular cell adenomas of the kidney. There was some evidence of carcinogenic activity of hydroquinone for female F344/N rats, as shown by increases in mononuclear cell leukemia. There was no evidence of carcinogenic activity of hydroquinone for male B6C3F1 mice administered 50 or 100 mg/kg in water by gavage. There was some evidence of carcinogenic activity of hydroquinone for female B6C3F1 mice, as shown by increases in hepatocellular neoplasms, mainly adenomas. Administration of hydroquinone was associated with thyroid follicular cell hyperplasia in both male and female mice and anisokaryosis, multinucleated hepatocytes, and basophilic foci of the liver in male mice. Synonyms: 1,4-benzenediol; p-benzenediol; benzohydroquinone; benzoquinol; 1,4-dihydroxybenzene; p-dihydroxybenzene; p-dioxobenzene; p-dioxybenzene; hydroquinol; hydroquinole; a-hydroquinone; p-hydroquinone; p-hydroxyphenol; quinol; b-quinol
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PMID:NTP Toxicology and Carcinogenesis Studies of Hydroquinone (CAS No. 123-31-9) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1269 38

1-Amino-2,4-dibromoanthraquinone is an anthraquinone-derived vat dye, a member of a class of insoluble dyes that are impregnated into textile fibers. Five anthraquinone-derived dyes with representative and diverse structures, as well as the parent chemical, anthraquinone, were selected for NTP Toxicology and Carcinogenesis evaluation. Similar to the benzidine dye initiative, the rationale for selecting these vat dyes was to generate sufficient toxicologic data to permit more reliable predictions of carcinogenicity to be made on other chemicals in this class, thereby eliminating or reducing the need to study every anthraquinone dye. 1-Amino-2,4-dibromoanthraquinone is the last anthraquinone-derived dye in this group to be studied. Groups of male and female F344/N rats and B6C3F1 mice were exposed to 1-amino-2,4-dibromoanthraquinone (87% to 97% pure) for 13 weeks or for 9, 15, or 24 months. Because 1-amino-2,4-dibromoanthraquinone was predicted to be carcinogenic, these studies were designed to evaluate the potential for tumor progression and regression. Absorption and excretion studies were carried out in male F344/N rats. Genetic toxicity was determined in vitro using Salmonella typhimurium and cultured Chinese hamster ovary cells. Extensive chemical analyses were performed to identify and characterize impurities of the 1-amino-2,4-dibromoanthraquinone used in these studies. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were given 0, 2,500, 5,000, 10,000, 25,000, or 50,000 ppm 1-amino-2,4-dibromoanthraquinone in feed for 13 weeks. These levels correspond to approximately 150 to 3,200 mg 1-amino-2,4-dibromoanthraquinone/kg body weight per day for males and to approximately 170 to 3,200 mg/kg for females. Chemical-related mortality was limited to one male and one female in the 50,000 ppm groups. Final mean body weights and body weight gains of all exposed groups of rats were significantly lower than those of the controls. Feed consumption by all exposed groups was less than that by the controls throughout the study and generally decreased with increasing exposure concentration. Pink-red staining of the fur and tail was observed in all exposed groups. Absolute and relative liver weights of all exposed groups were generally significantly greater than those of the controls. Chemical-related lesions were present in the liver, kidney, and spleen of male and female rats. Nonneoplastic lesions in the liver included foci of hepatocellular alteration, diffuse hepatocellular hypertrophy (cytomegaly), hepatocellular cytoplasmic vacuolation, bile duct hyperplasia, inflammation, and pigmentation. These differences were observed primarily in the 25,000 and 50,000 ppm groups of males and females; the spectrum of proliferative lesions of the bile ducts (hyperplasia, fibrosis, and necrotizing cholangitis) in the 25,000 and 50,000 ppm groups was morphologically consistent with the lesion described as cholangiofibrosis. Pigmentation was present in the renal tubule epithelium of all groups of exposed rats; nuclear enlargement (karyomegaly) was also present in the renal tubule epithelium in some of the exposed rats. Accumulation of hyaline droplets in the cytoplasm of the renal tubule epithelium and tubule lumina was present in 2,500, 5,000, 10,000, and 25,000 ppm males. Incidences of hematopoiesis of the spleen in exposed groups of males and females were increased compared to those in the controls. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were given 0, 2,500, 5,000, 10,000, 25,000, or 50,000 ppm 1-amino-2,4-dibromoanthraquinone in feed for 13 weeks. These levels correspond to approximately 500 to 10,600 mg 1-amino-2,4-dibromoanthraquinone/kg body weight per day for males and approximately 660 to 11,700 mg/kg per day for females. There was no chemical-related mortality. Feed consumption and final mean body weights of exposed groups were similar to those of the controls. Red staining of the fur was observed in all exposed groups. Absolute and relative liver weights of the exposed groups were greater than those er than those of the controls except for the absolute liver weight of 2,500 ppm males. Absolute and relative kidney weights of 25,000 and 50,000 ppm males were lower than those of the controls. Chemical-related lesions were limited to the livers of males and consisted of pigmentation of hepatocytes at all exposure concentrations and centrilobular hepatocellular hypertrophy at 10,000, 25,000, and 50,000 ppm. Minimal pigment was present in the liver of one female in the 25,000 ppm group and in one female in the 50,000 ppm group. 2-YEAR STUDY IN RATS: Groups of 70 male and 70 female rats were given 0, 5,000, or 10,000 ppm 1-amino-2,4-dibromoanthraquinone in feed for 103 weeks. In addition, groups of 50 male and 50 female rats were given 2,000 ppm 1-amino-2,4-dibromoanthraquinone in feed for 104 weeks. These exposure concentrations were approximately equal to 90, 240, or 490 mg 1-amino-2,4-dibromoanthraquinone/kg body weight for males and 110, 285, or 600 mg/kg for females. Ten animals from each group were evaluated for histopathology at 9 months. Additional groups of 10 animals from the 0 and 10,000 ppm groups were evaluated for histopathology at 15 months. Survival, Body Weights, Feed Consumption, and Clinical Findings In the 2-year study, survival of the 10,000 ppm males and females was significantly lower than that of the controls. Survival of the 2,000 and 5,000 ppm groups was similar to that of the controls. During the last year of the study, the mean body weights of exposed males were 80% to 91% those of controls, and the mean body weights of exposed females were 67% to 84% those of controls. Feed consumption among exposed groups was generally similar, but was less than that by controls. The fur and urine of all exposed male and female groups were discolored. Pathology Findings In the 2-year study, 1-amino-2,4-dibromoanthraquinone was associated with significant chemical-related increases in the incidences of benign and malignant neoplasms in the liver, large intestine, kidney, and urinary bladder of males and females. Chemical-related nonneoplastic proliferative and degenerative lesions occurred in the liver, kidney, urinary bladder, and forestomach of males and females. The incidences of foci of hepatocellular alteration and pigmentation in the liver of males and females were increased at the 9-month interim evaluation, and a hepatocellular adenoma was present in one 5,000 ppm male. At the 15-month interim evaluation, hepatocellular adenoma or carcinoma (combined) occurred in all males and nine females in the 10,000 ppm groups. By the end of the 2-year study, hepatocellular adenoma, carcinoma, cholangioma, or cholangiocarcinoma were observed in males and females in the 5,000 and 10,000 ppm groups. In the 2,000 ppm groups, similar liver neoplasms were present in 63% of the males and in 83% of the females. Of the hepatocellular carcinomas in the 5,000 and 10,000 ppm groups of males and females, 31% to 49% were metastatic to the lungs or other sites. Increases in the incidences of foci of hepatocellular alteration (basophilic, eosinophilic, and clear cell) and pigmentation of the liver were also observed in exposed groups of males and females. Adenomatous polyps (adenoma) of the large intestine were present in six 10,000 ppm males at the 15-month interim evaluation. Incidences of adenomatous polyp (adenoma) and carcinoma of the large intestine were significantly increased in exposed groups of males and females after 2 years; multiple benign and malignant intestinal neoplasms were observed in many of these rats. In the kidney, incidences of renal tubule adenoma and carcinoma were significantly increased in exposed groups of males and females after 2 years. Renal tubule adenomas were present in two 10,000 ppm males at 15 months. There were also chemical-related increases in the incidences and severities of renal tubule epithelial hyperplasia, pigmentation, and transitional cell hyperplasia in the kidney of males and females. Hyaline droplet accumulation was present in all exposed male rats at 9 months. Incidences of transitional cell papilloma and carcinoma of the urinary bladder were increased at 2 years in males and females in the 10,000 ppm groups. Transitional cell hyperplasia was observed in exposed males and females at the 15-month interim evaluation. Other nonneoplastic lesions observed in the urinary bladder at 2 years included metaplasia of the transitional epithelium and submucosal stromal tissue. In the forestomach, the incidences and severities of inflammation, ulceration, hyperkeratosis, and hyperplasia of the squamous mucosa were increased in all exposed groups of males and females at 2 years, but not at the 9- or 15-month interim evaluations. In exposed males and females, the incidences of mononuclear cell leukemia were significantly decreased. The incidences of atrophy of the seminal vesicle were increased in exposed male rats in the 2-year study. Stop-Exposure Evaluation in Rats Groups of 40 male and 40 female rats were given 20,000 ppm 1-amino-2,4-dibromoanthraquinone in feed for 9 or 15 months. At 9 months, 10 males and 10 females were evaluated for histopathology (9-month interim evaluation groups). After 9 months of exposure, an additional 10 males and 10 females were fed control diet until the end of the 15-month evaluation (9-month stop-exposure groups), and 20 males and 20 females continued to receive 20,000 ppm 1-amino-2,4-dibromoanthraquinone until the end of the evaluation (15-month exposure groups). The approximate daily consumption of 1-amino-2,4-dibromoanthraquinone was 1,335 mg/kg for males and 1,790 mg/kg for females in the 9-month stop-exposure groups and 1,115 mg/kg for males and 1,435 mg/kg for females in the 15-month exposure groups. Survival was similar among groups except for the females in the 15-month exposure group; the survival of this group was lower than that of the controls. Lower mean body weights were related to increased exposure duration. The mean body weights of exposed males were 76% to 82% that of controls, and the mean body weights of exposed females were 73% to 84% that of controls. For the stop-exposure evaluation, similar chemical-related neoplasms and nonneoplastic lesions were observed in the same sites as in the 2-year study: liver, large intestine, kidney, urinary bladder, and forestomach. After 9 months of dietary exposure to a concentration of 20,000 ppm 1-amino-2,4-dibromoanthraquinone, hepatocellular adenoma and carcinoma occurred in males and females. Nonneoplastic chemical-related lesions in the liver of exposed rats included pigmentation, focal hepatocellular alteration, and bile duct hyperplasia. Neoplasms at other sites in males included one adenomatous polyp (adenoma) in the large intestine and one transitional cell papilloma in the urinary bladder. Hyaline droplet accumulation was present in the kidney of exposed males at 9 months. In the stop-exposure groups examined at 15 months, hepatocellular adenoma and carcinoma were present in most males and females. Adenomatous polyp (adenoma) of the colon, renal tubule cell adenoma, and urinary bladder transitional cell papilloma and carcinoma also occurred in males and females. Nonneoplastic chemical-related lesions included foci of hepatocellular alteration in the liver and hyperplasia of the renal tubule epithelium and urinary bladder transitional epithelium. Hyperplasia, hyperkeratosis, inflammation, and ulceration were observed in the forestomach of some male and female rats continuously exposed for 15 months. 2-YEAR STUDY IN MICE: Groups of 60 male and 60 female mice were given 0, 10,000, or 20,000 ppm 1-amino-2,4-dibromoanthraquinone in feed for 104 weeks. The daily compound consumption was approximately 1,690 or 3,470 mg 1-amino-2,4-dibromoanthraquinone/kg body weight for males and 1,950 or 4,350 mg/kg for females. Ten animals from each group were evaluated for histopathology at 15 months. Survival, Body Weights, Feed Consumption, and Clinical Findings In the 2-year study, survival of exposed males was significantly lower than that of the controls. Survival of exposed females was similar to that of the controls. The final mean body weights of exposed males were 83% to 85% that of controls, and the final mean body weights of exposed females were 81% to 86% that of controls. Feed consumption by exposed groups was generally similar to that by controls. Discoloration of the fur, urine, and feces was observed in all exposed groups. Pathology Findings In the 2-year study, 1-amino-2,4-dibromoanthraquinone was associated with significant chemical-related increases in the incidences of benign and malignant neoplasms in the liver, forestomach, and lung of males and females. Incidences of hepatocellular adenoma and carcinoma were increased in exposed groups at the 15-month interim evaluation and at 2 years. At 2 years, there were significant increases in the incidences of multiple hepatocellular adenoma and carcinoma in males and females and in the incidences of hepatoblastoma in males. Centrilobular hypertrophy of hepatocytes in males and foci of hepatocellular alteration and pigmentation in the liver of males and females were also chemical-related changes. Sqamous cell papilloma of the forestomach mucosa occurred in 10,000 ppm females and 20,000 ppm males and females at the 15-month interim evaluation, and the incidences of squamous cell papilloma and carcinoma were significantly increased in exposed groups of males and females at 2 years. Chemical-related hyperplasia of forestomach epithelium was also present at 15 months and at 2 years. Alveolar/bronchiolar adenomas were present only in the exposed groups of males and females at 15 months, and the incidences of alveolar/bronchiolar adenoma were significantly increased in exposed males and females at 2 years. The incidences of multiple alveolar/bronchiolar adenomas were also increased in exposed males. In the kidney, pigmentation was present in the renal tubules of most mice after 2 years of exposure. DISPOSITION AND METABOLISM STUDIES: Adult male F344/N rats were given [14C]-labeled 1-amino-2,4-dibromoanthraquinone as a single intravenous dose of 0.4 mg/kg body weight or as a single oral dose of 2, 23, 118, 814, or 1,473 mg/kg. A 6-hour bile cannulation study was also performed. From day 0 through day 3 after intravenous administration, about 50% of the 14C was excreted in the feces, 15% in the urine, and 6% in expired air. Unmetabolized 1-amino-2,4-dibromoanthraquinone accounted for less than 3% of the excreted 14C after intravenous administration. For oral doses administered, the amount of the dose that was absorbed fit the equation: absorbed dose = 6.6 x log(dose). After intravenous administration, the metabolites of 1-amino-2,4-dibromoanthraquinone in blood were primarily in the plasma fraction (blood:plasma ratio of approximately 0.5:1). The highest concentrations of 14C in tissues 15 minutes after intravenous dosing were in excretory organs, lung, kidney, small intestine, liver, adipose tissue, and adrenal gland. GENETIC TOXICOLOGY: 1-Amino-2,4-dibromoanthraquinone was mutagenic in Salmonella typhimurium strains TA98 and TA1537 in the absence of S9; with S9, an equivocal response was observed in TA1537. 1-Amino-2,4-dibromoanthraquinone resulted in an equivocal response in TA100 with and without S9, and no mutagenic activity was detected with strain TA1535. In cultured Chinese hamster ovary cells, 1-amino-2,4-dibromoanthraquinone induced sister chromatid exchanges with and without S9; chromosomal aberrations were induced in the absence of S9. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was clear evidence of carcinogenic activity of 1-amino-2,4-dibromoanthraquinone in male and female F344/N rats based on increased incidences of neoplasms in the liver, large intestine, kidney, and urinary bladder. There was clear evidence of carcinogenic activity of 1-amino-2,4-dibromoanthraquinone in male and female B6C3F1 mice based on increased incidences of neoplasms in the liver, forestomach, and lung. Exposure of male and female rats to 1-amino-2,4-dibromoanthraquinone for 2 years was associated with basophilic focus (males only), clear cell focus, eosinophilic focus, and pigmentation in the liver; renal tubule hyperplasia, renal tubule pigmentation, and transitional cell hyperplasia in the kidney; transitional cell hyperplasia, squamous metaplasia, and stromal metaplasia (females only) in the urinary bladder; squamous hyperplasia, hyperkeratosis, ulceration, and inflammation of the forestomach mucosa; and seminal vesicle atrophy. Exposure of male and female mice to 1-amino-2,4-dibromoanthraquinone for 2 years was associated with centrilobular hepatocellular hypertrophy (males only), basophilic focus, clear cell focus (females only), eosinophilic focus, and pigmentation in the liver; pigmentation in the kidney; and hyperplasia, basal cell hyperplasia, hyperkeratosis, and inflammation of the forestomach mucosa. Synonym: ADBAQ
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PMID:NTP Toxicology and Carcinogenesis Studies of 1-Amino-2,4-Dibromoanthraquinone (CAS No. 81-49-2) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1269 53

Methyl carbamate is used as a chemical intermediate by the textile industry for the manufacture of dimethylol methyl carbamate-based resins that are applied on polyester/cotton blend fabrics as durable-press finishes. Experimental Design: Toxicology and carcinogenesis studies of methylyl carbamate (98% pure) were conducted by exposing groups of F344/N rats and B6C3F1 mice by gavage in water in a single dose and by repeated administration for 16 days, 13 weeks, 6 months, 12 months, 18 months, and 2 years. In addition, short-term mutagenicity studies in bacteria, mammalian cells, and Drosophila and of unscheduled DNA synthesis in rat liver cells were conducted. Single-Administration Studies: In the single-administration studies, 5/5 male and 5/5 female rats that received 8,000 mg/kg methyl carbamate and 2/5 male and 5/5 female that received 4,000 mg/kg died before the end of the 15-day observational period. Five of five male and 5/5 female mice that received 8,000 mg/kg and 1/5 females that received 4,000 mg/kg died before the end of the 15-day observational period. No compound-related morphologic effects were observed in rats or mice that received 2,000 mg/kg. Sixteen-Day Studies: In the 16-day studies, all rats dosed at 2,000 or 4,000 mg/kg died, and 3/5 male rats that received 1,000 mg/kg died. Male mice that received 2,000 or 4,000 mg/kg, female mice that received 4,000 mg/kg, and 1/5 female mice that received 2,000 mg/kg died. No compound-related gross pathologic or histopathologic effects were seen in male or female rats (groups of five each) that received 500 mg/kg or in mice that received 1,000 mg/kg. Thirteen-Week Studies: In the 13-week studies, groups of 10 male and 10 female rats and mice received up to 800 mg/kg (male rats), 1,000 mg/kg (female rats), 1,500 mg/kg (male mice), or 2,000 mg/kg (female mice). Four of 10 male rats that received 800 mg/kg and 1/10 female rats that received 1,000 mg/kg died of compound-related causes before the end of the studies. Toxic hepatitis, splenic pigmentation, bone marrow atrophy, and testicular atrophy were observed in the two highest dose groups of rats. One of the female mice that received 2,000 mg/kg died. The dosed female mice had significantly greater liver weights than did the vehicle controls. Experimental Design of Six-, Twelve-, and Eighteen-Month and Two-Year Studies: Based on the findings in the short-term studies, 2-year studies of methyl carbamate were conducted by administering 0, 100, or 200 mg/kg methyl carbamate in distilled water by gavage, 5 days per week for 103 weeks, to groups of 50 F344/N rats of each sex for 103 weeks. Groups of 50 B6C3F1 mice of each sex were administered 0, 500, or 1,000 mg/kg methyl carbamate on the same schedule. Additional groups of 30 rats of each sex were administered 0 or 400 mg/kg methyl carbamate, and additional groups of 30 mice of each sex were administered 0 or 1,000 mg/kg methyl carbamate in distilled water by gavage, 5 days per week. Ten animals from each group were killed at 6, 12, or 18 months so that the progression of lesions could be followed. Results of the Six-, Twelve-, and Eighteen-Month and Two-Year Studies: In the 6-month studies, all vehicle control and dosed (400 mg/kg) rats survived. Cytologic alterations and atypical proliferative changes were observed in the liver of all dosed male and female rats, and neoplastic nodules of the liver were observed in 6/10 dosed male and 5/10 dosed female rats. In the 12-month studies, all vehicle control male and female rats and dosed female rats survived. One of 10 dosed male rats died. Neoplastic nodules of the liver were observed in 7/10 dosed male and 9/10 dosed female rats, and hepatocellular carcinomas were observed in 8/10 dosed male and 6/10 dosed female rats. In the 18-month studies, 1/10 dosed male and 8/10 dosed female and all vehicle control rats survived. Hepatocellular carcinomas were observed in 9/10 dosed male and 8/10 dosed female rats. Compound-related neoplastic changes were not observed in mice in the 6-, 12-, or 18-month studies. In the 2-year studar studies, mean body weights of high dose (200 mg/kg) male rats were generally 5%-9% lower than those of the vehicle controls after week 20. Mean body weights of high dose female rats were 5%-8% lower than those of the vehicle controls after week 56. Survival of dosed and vehicle control rats was similar (male: vehicle control, 19/50; low dose, 26/50; high dose, 29/50; female: 29/50; 36/50; 35/50). The mean body weights of high dose (1,000 mg/kg) male mice were about 8%-18% lower than those of the vehicle controls after week 24. The mean body weights of high dose (1,000 mg/kg) female mice were about 16% lower than those of the vehicle controls after week 16 and 30% lower after week 64. Survival of dosed and vehicle control mice was similar (male: 28/50; 35/50; 28/50; female: 38/50; 36/50; 32/50). Chronic focal inflammation and cytologic alteration of the liver were observed at increased incidences in high dose rats of each sex. Hyperplasia of hepatocytes was observed atincreased incidences in dosed male and high dose female rats. Neoplastic nodules or hepatocellular carcinomas (combined) in female rats occurred with a significant positive trend (0/50; 0/50; 6/49; P<0.01); the incidence of neoplastic nodules or hepatocellular carcinomas (combined) in high dose female rats was greater (P<0.03) than that in the vehicle controls. Incidences of liver neoplasms in dosed male rats were not significantly increased (4/50; 0/50; 7/49). Inflammation of the harderian gland was observed at increased incidences in dosed rats (male: 4/50; 11/50; 16/50; female: 7/50; 16/50; 30/50). The lesions were considered to be chemically related. In the 2-year studies in rats, significant decreases in tumor incidences included the following: leukemia (both sexes), pituitary gland (male), adrenal gland (male), and mammary gland (female). In the 2-year mouse studies, multinucleate giant cells in the liver were observed at increased incidences in dosed male mice (14/50; 31/50; 31/49). Adenomatous hyperplasia and histiocytosis of the lung were observed at increased incidences in high dose mice (adenomatous hyperplasia--male: 13/50; 19/50; 24/49; female: 7/49; 10/50; 18/50; histiocytosis--male: 11/50; 7/50; 21/49; female: 9/49; 10/50; 21/50). Genetic Toxicology: Methyl carbamate was not mutagenic in Salmonella typhimurium strains TA97, TA98, TA100, or TA1535 when tested with or without metabolic activation in a preincubation protocol at doses up to 10 mg/plate. Methyl carbamate did not induce forward mutations in the mouse L5178Y/TK± lymphoma assay with or without metabolicactivation at doses up to 5 mg/ml. Unscheduled DNA synthesis was not detected in rat hepatocytes after in vitro treatment with methyl carbamate at concentrations of 1.0-1,000 ug/ml. When tested in Drosophila at doses of 25,000-50,000 ppm, methyl carbamate did not induce sex-linked recessive lethal mutations. Results of tests for induction of chromosomal aberrations and sister chromatid exchanges by methyl carbamate in cultured Chinese hamster ovary cells were also negative at doses up to 5 mg/ml. Data Audit: An audit of the experimental data was conducted for the 6-, 12-, and 18-month and 2-year studies of methyl carbamate. No data discrepancies were found that influenced the final interpretation. Conclusions: Under the conditions of these 6-, 12-, and 18-month and 2-year gavage studies, there was clear evidence of carcinogenic activity for male and female F344/N rats given methyl carbamate as indicated by increased incidences of hepatocellular neoplastic nodules and hepatocellular carcinomas. There was no evidence of carcinogenic activity for male and female B6C3F1 mice given methyl carbamate at doses of 500 or 1,000 mg/kg. Methyl carbamate also induced inflammation of the harderian gland in male and female rats and adenomatous hyperplasia and histiocytosis of the lung in male and female mice. Synonyms: carbamic acid, methyl ester; methylurethan; methylurethane; urethylane
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PMID:NTP Toxicology and Carcinogenesis Studies of Methyl Carbamate (CAS No. 598-55-0) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1273 8

Benzene ranks 16th in production volume for chemicals produced in the United States, with approximately 9.9 billion pounds being produced in 1984, 9.1 billion pounds in 1983, and 7.8 billion pounds in 1982. This simplest aromatic chemical in used in the synthesis of styrene (polystyrene plastics and synthetic rubber), phenol (phenolic resins), cyclohexane (nylon), aniline, maleic anhydride (polyester resins), alkylbenzenes (detergents), chlorobenzenes, and other products used in the production of drugs, dyes, insecticides, and plastics. Benzene, along with other light, high-octane aromatic hydrocarbons, such as toluene and xylenes, is a component of motor gasoline. Benzene is also used as a solvent, but for most applications, it has been replaced by less hazardous solvents. During the 17-week studies, groups of 10 or 15 male and female F344/N rats and B6C3F1 mice were gavaged 5 days per week with benzene in corn oil (5 ml/kg) at doses of 0 to 600 mg/kg. No benzene-related deaths occurred; in rats that received benzene, final mean body weights were 14%-22% lower compared with vehicle controls and in mice, slight dose-related reductions were observed (less than 10% differences). Doses for the 2-year studies were selected based on clinical observations (tremors in higher dosed mice), on clinical pathologic findings (lymphoid depletion in rats and leukopenia in mice), and on body weight effects. Two-year toxicology and carcinogenesis studies of benzene (greater than 99.7% pure) were conducted in groups of 50 F344/N rats and 50 B6C3F1 mice of each sex and for each dose. Doses of 0, 50, 100, or 200 mg/kg body weight benzene in corn oil (5 ml/kg) were administered by gavage to male rats, 5 days per week, for 103 weeks. Doses of 0, 25, 50, or 100 mg/kg benzene in corn oil were administered by gavage to female rats and to male and female mice for 103 weeks. Ten additional animals in each of the 16 groups were killed at 12 months and necropsies were performed. Hematologic profiles were performed at 3-month intervals. These studies were designed and conducted because of large production volume and potential human exposure, because of the epidemiologic association with leukemia, and because previous experiments were considered inadequate or inconclusive for determining potential carcinogenicity in laboratory animals. In the 2-year studies, mean body weights of the 200 mg/kg male rats (-23%) and the 100 mg/kg mice (-14% to -19%) were lower than those of the vehicle controls, and survival of dosed groups decreased with increasing dose (rats--male: vehicle control, 32/50; low dose, 29/50; mid dose, 25/50; high dose, 16/50; female: 46/50; 38/50; 34/50; 25/50; mice--male: 28/50; 23/50; 18/50; 7/50; female: 30/50; 26/50; 24/50; 18/50). At week 92 for rats and week 91 for mice, survival was greater than 60% in all groups; most of the dosed animals that died before week 103 had neoplasia. Compound-related nonneoplastic or neoplastic effects on the hematopoietic system, Zymbal gland, forestomach, and adrenal gland were found both for rats and mice. Further, the oral cavity was affected in rats, and the lung, liver, harderian gland, preputial gland, ovary, and mammary gland were affected in mice. Significantly increased (P<0.05) incidences of neoplasms were observed at multiple sites for male and female rats and for male and female mice. Primary neoplasms observed in rats and mice are summarized in Table 1 (see page 12 of the Technical Report). Hematologic data from vehicle control and dosed rats and mice were obtained at 3-month intervals from 0 to 24 months. Reliably identifiable hematologic effects were limited to lymphocytopenia and associated leukocytopenia in benzene-dosed rats and mice. These effects were seen from 3 to 18 months in dosed male rats and in dosed male mice; a similar but less pronounced response was observed in dosed female rats during this same time period. The effect in female mice was limited to 12-18 months. The technical quality of certain of these data was questionable; thus, more detailed analyses (e.g., investig questionable; thus, more detailed analyses (e.g., investigation of the association between hematologic and pathologic changes) are deemed inappropriate for these data. Benzene increased the frequency of micronucleated normchromatic peripheral erythrocytes in male and female mice (rats were not examined); males were more sensitive than females. The hematopoietic system of rats and mice of each sex was affected by benzene in the 2-year studies. The incidences of malignant lymphomas in all dosed groups of mice were greater than those in the vehicle controls (male: 4/49; 9/48; 9/50; 15/49; female: 15/49; 24/45; 24/50; 20/49). Lymphoid depletion of the splenic follicles (rats) and thymus (male rats) was observed at increased incidences. Bone marrow hematopoietic hyperplasia was observed at increased incidences in dosed mice of each sex (male: 0/49; 11/48; 10/50; 25/49; female: 3/49; 14/45; 8/50; 13/49). The incidences of Zymbal gland carcinomas in mid and high dose male rats and in dosed female rats were greater than those in the vehicle controls (male: 2/32; 6/46; 10/42; 17/42; female: 0/45; 5/40; 5/44; 14/46). The incidences of Zymbal gland carcinomas in mid and high dose male mice and in high dose female mice were greater than those in the vehicle controls (male: 0/43; 1/34; 4/40; 21/39; female: 0/43; 0/32; 1/37; 3/31). In mid and high dose male mice and in high dose female mice, the incidences of epithelial hyperplasia of the Zymbal gland were also increased (male: 0/43; 3/34; 12/40; 10/39; female: 1/43; 1/32; 2/37; 6/31). Hyperplasia of the adrenal capsule was observed at increased incidences in dosed mice of each sex (male: 2/47; 32/48; 14/49; 4/46; female: 5/49; 19/44; 34/50; 30/48). The incidence of pheochromocytomas in mid dose male mice was greater than that in the vehicle controls (male: 1/47; 1/48; 7/49; 1/46), whereas the incidences in dosed female mice were lower than that in the vehicle controls (female: 6/49; 1/44; 1/50; 1/48). Hyperplasia of the zona fasciculata of the adrenal cortex was observed at increased incidences in low dose rats of each sex (male: 0/50; 13/49; 0/48; 2/49; female: 0/50; 17/50; 0/47; 0/49). Benzene was associated with increased incidences of neoplasms of the skin and oral cavity of rats. The incidences of squamous cell papillomas and squamous cell carcinomas of the skin in high dose male rats were greater than those in the vehicle controls (squamous cell papilloma: 0/50; 2/50; 1/50; 5/50; squamous cell carcinoma: 0/50; 5/50; 3/50; 8/50). Increased incidences of uncommon squamous cell papillomas or squamous cell carcinomas (combined) of the oral cavity were observed in dosed male and female rats (male: 1/50; 9/50; 16/50; 19/50; female: 1/50; 5/50; 12/50; 9/50). Incidences of squamous cell papillomas or carcinomas (combined) (male: 2/45; 2/42; 3/44; 5/38; female: 1/42; 3/40; 6/45; 5/42), hyperkeratosis, and epithelial hyperplasia of the forestomach were increased in some dosed groups of male and female mice; incidences of hyperkeratosis and acanthosis were increased in high dose male rats. Compound-related effects in the lung, harderian gland, preputial gland, ovary, mammary gland, and liver were seen in mice but not in rats. Administration of benzene was associated with increased incidences of alveolar epithelial hyperplasia in mid and high dose mice (male: 2/49; 3/48; 7/50; 10/49; female: 1/49; 1/42; 9/50; 6/49). Increased incidences of alveolar/bronchiolar carcinomas and alveolar/bronchiolar adenomas or carcinomas (combined) were observed in high dose male mice (carcinomas: 5/49; 11/48; 12/50; 14/49; adenomas or carcinomas: 10/49; 16/48; 19/50; 21/49). Alveolar/bronchiolar adenomas were seen at increased incidences in high dose female mice (4/49; 2/42; 5/50; 9/49), as were alveolar/bronchiolar carcinomas (0/49; 3/42; 6/50; 6/49) and alveolar/bronchiolar adenomas or carcinomas combined (4/49; 5/42; 10/50; 13/49) in mid and high dose female mice. The incidences of focal or diffuse hyperplasia of the harderian gland were increased in dosed mice of each sex (male: 0/49; 5/46; 11/49; 7/48; female: 6/48; 10/44; 11/50; 10/47). The incidences of harderian gland adenomas (0/49; 9/46; 13/49; 11/48) in dosed male mice were greater than that in the vehicle controls. A marginal increase in the incidence of adenomas or carcinomas (combined) of the harderian gland was seen in high dose female mice (5/48; 6/44; 10/50; 10/47). The administration of benzene to male mice was associated with increased incidences of hyperplasia (1/21; 18/28; 9/29; 1/35) and squamous cell carcinomas (0/21; 3/28; 18/29; 28/35) of the preputial gland. Increased incidences of mammary gland carcinomas were found in mid dose and high dose female mice (0/49; 2/45; 5/50; 10/49) and carcinosarcomas in high dose female mice (0/49; 0/45; 1/50; 4/49). Increased incidences of various uncommon neoplastic and nonneoplastic lesions of the ovary (papillary cystadenoma, luteoma, granulosa cell tumor, tubular adenoma, benign mixed tumor, epithelial hyperplasia, and senile atrophy) were associated with the administration of benzene to female mice. In mid and high dose female mice, the incidences of granulosa cell tumors (1/47; 1/44; 6/49; 7/48) and benign mixed tumors (0/47; 1/44; 12/49; 7/48) were greater than those in the vehicle controls. Increased incidences of hepatocellular adenomas were observed in low dose female mice (1/49; 8/44; 5/50; 4/49) and hepatocellular adenomas or carcinomas (combined) in low dose and mid dose female mice (4/49; 12/44; 13/50; 7/49). An audit of the experimental data was conducted for these 2-year carcinogenesis studies on benzene. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenicity of benzene for male F344/N rats, for female F344/N rats, for male B6C3F1 mice, and for female B6C3F1 mice. For male rats, benzene caused increased incidences of Zymbal gland carcinomas, squamous cell papillomas and squamous cell carcinomas of the oral cavity, and squamous cell papillomas and squamous cell carcinomas of the skin. For female rats, benzene caused increased incidences of Zymbal gland carcinomas and squamous cell papillomas and squamous cell carcinomas of the oral cavity. For male mice, benzene caused increased incidences of Zymbal gland squamous cell carcinomas, malignant lymphomas, alveolar/bronchiolar carcinomas and alveolar/bronchiolar adenomas or carcinomas (combined), harderian gland adenomas, and squamous cell carcinomas of the preputial gland. For female mice, benzene caused increased incidences of malignant lymphomas, ovarian granulosa cell tumors, ovarian benign mixed tumors, carcinomas and carcinosarcomas of the mammary gland, alveolar/bronchiolar adenomas, alveolar/bronchiolar carcinomas, and Zymbal gland squamous cell carcinomas. Dose-related lymphocytopenia was observed for male and female F344/N rats and male and female B6C3F1 mice. Synonyms: benzol, cyclohexatriene, pyrobenzol
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PMID:NTP Toxicology and Carcinogenesis Studies of Benzene (CAS No. 71-43-2) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1274 14


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