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National Toxicology Program

Publications and source records attributed to National Toxicology Program.

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PubMed1991

NTP Toxicology and Carcinogenesis Studies of Titanocene Dichloride (CAS No. 1271-19-8) in F344/N Rats (Gavage Studies).

Titanocene dichloride is an organometallic compound composed of two cyclopentadienyl rings, titanium, and chloride. It is used as a cocatalyst in polymerization reactions. Toxicology and carcinogenesis studies were conducted by administering titanocene dichloride (greater than 98% pure) in corn oil by gavage to groups of F344/N rats for 14 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and in Chinese hamster ovary cells. 14-Day and 13-Week Studies: In the 14-day studies, titanocene dichloride was administered at doses of 0, 65, 125, 250, 500, or 1,000 mg/kg. All high-dose rats and four of the five male and two of the five female rats given 500 mg/kg died during the studies. A dose-related decrease in body weight gain was seen in rats given 125, 250, 500, and 1,000 mg/kg. Lesions related to chemical administration included hepatocellular necrosis, tubule necrosis in the kidney, erosions and ulcers of the glandular stomach, and hyperplasia of the forestomach epithelium. The 13-week studies were conducted by administering titanocene dichloride at doses of 0, 8, 16, 31, 62, or 125 mg/kg. One female rat in the 125 mg/kg dose group died from chemical toxicity during the fourth week of the studies. Body weight gain was lower in rats given 62 or 125 mg/kg than in control groups. Treatment-associated histopathologic lesions were seen in the stomachs of high-dose males and all groups of females given titanocene dichloride. These lesions included hyperplasia and metaplasia of the glandular stomach and hyperplasia and hyperkeratosis of the forestomach. Body Weight and Survival in the 2-Year Studies: The doses selected for the 2-year studies in rats (0, 25, and 50 mg/kg) were based on the potentially life-threatening nature of the glandular stomach lesions and the decreased body weight gain compared to controls seen in the 62 and 125 mg/kg dose groups in the 13-week studies. The final mean body weights of high-dose males and females were 91% and 89% of controls, respectively. The 2-year survival rates for males in the control, low-, and high-dose groups were 41/60, 30/60, and 24/60; survival rates for female rats were 37/60, 30/61, and 31/60. Nonneoplastic and Neoplastic Effects in the 2-Year Studies: The principal toxic effects associated with the administration of titanocene dichloride for 2 years occurred in the stomach. The lesions in the stomach were seen at the 15-month interim evaluations and were similar to, but less severe than, those observed at 2 years. The lesions included focal erosions of the glandular mucosa with an associated inflammatory response, hyperplasia and metaplasia of the epithelium of the fundic glands, and fibrosis of the lamina propria and submucosa. Forestomach lesions included focal acanthosis (hyperplasia) and hyperkeratosis of the stratified squamous epithelium. Squamous cell papillomas of the forestomach were seen in four low-dose males, one high-dose male, one low-dose female, and two high-dose females; none were observed in controls. A squamous cell carcinoma of the forestomach occurred in one low-dose male and a benign basosquamous tumor occurred in one high-dose male. Accumulations of macrophages with blue-gray pigment believed to contain titanium were present in many organs of dosed rats including the gastrointestinal tract, liver, lung, and lymph nodes. A dose-related increase in the incidence of inflammation of the nasal mucosa and lung also occurred and was attributed to reflux and/or regurgitation and aspiration of gavage solution due to the severe stomach lesions. Genetic Toxicology: Titanocene dichloride was mutagenic in Salmonella typhimurium strain TA100 in the absence of exogenous metabolic activation (S9); it was not mutagenic in TA100 with S9, nor was it mutagenic in TA1535, TA1537, or TA98 with or without S9. Titanocene dichloride did not induce sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells, with or without S9. Conclusions: Under the conditions of these 2-year gavage studies, there was equivocal, there was equivocal evidence of carcinogenic activity of titanocene dichloride in male F344/N rats based on a marginal increase in the incidence of forestomach squamous cell papillomas, squamous cell carcinoma, and basosquamous tumor benign. There was equivocal evidence of carcinogenic activity of titanocene dichloride in female F344/N rats based on a marginal increase in the incidence of forestomach squamous cell papillomas. Nonneoplastic lesions associated with the administration of titanocene dichloride for up to 2 years included erosions and inflammation of the gastric mucosa, hyperplasia and metaplasia of the fundic glands with fibrosis of the lamina propria in the glandular stomach, and acanthosis (hyperplasia) and hyperkeratosis of the forestomach epithelium. Synonyms: Titanium ferrocene; biscyclopentadienyltitanium dichloride; dichlorodi-p-cyclopentadienyltitanium; dichlorobis(h5-2,4-cyclopentadien-1-yl)titanium; dicyclopentadienyltitanium dichloride; dichlorodicyclopentadienyltitanium; dichlorotitanocene; dicyclopentadienyldichlorotitanium; dichlorobis(p-cyclopentadienyl)titanium; bis (h5-cyclopentadienyl) titanium dichloride; dichlorobis(h5-cyclopentadienyl)titanium; dichlorobiscyclopentadienyl titanium; dichlorobis(1,3-cyclopentadiene)titanium; bis(cyclopentadienyl)dichlorotitanium

Journal Article↗
PubMed1991

NTP Toxicology and Carcinogenesis Studies of Probenecid (CAS No. 57-66-9) in F344/N Rats and B6C3F1 (Gavage Studies).

Probenecid is a white crystalline solid commonly used as a uricosuric agent in the treatment of gout. Because of its inhibitory effects on renal tubule transport processes, probenecid is also used as a therapeutic adjunct to enhance blood levels of penicillin and its action. Toxicology and carcinogenicity studies were conducted by administering probenecid (>99% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex once daily, 5 days per week in 14-day, 13-week, and 2-year studies. Genetic toxicology studies were conducted in Salmonella typhimurium and Chinese hamster ovary cells. 14-Day Studies: Doses used in the 14-day studies for both rats and mice were 0, 200, 400, 800, 1,600, or 3,200 mg/kg. Of the animals receiving 3,200 mg/kg, all rats, all female mice, and two of five male mice died during the studies. No deaths occurred among the other dose groups. There was a significant reduction in body weight gain in male and female rats receiving 1,600 mg/kg and in female rats receiving 800 mg/kg. No gross lesions were attributed to probenecid administration in rats or mice of either sex. 13-Week Studies: Doses used in the 13-week studies were 0, 50, 100, 200, 400, or 800 mg/kg for rats and 0, 100, 200, 400, 800, or 1,600 mg/kg for mice. No rats died during the 13-week studies. In mice, 5 of 10 males and 3 of 10 females receiving 1,600 mg/kg and 1 of 10 males receiving 800 mg/kg died during the study. Significant reductions in body weight gain occurred in male rats administered 800 mg/kg, male mice administered 1,600 mg/kg, and female mice administered 800 or 1,600 mg/kg. All dose groups of male rats and all groups of female rats receiving 100 mg/kg or more showed significant increases in absolute and/or relative liver weights compared to control groups. This change was also seen in mice receiving 200 mg/kg and greater, except female mice in the 400 mg/kg group. No compound-related lesions occurred in rats or mice of either sex. Based on compound-related deaths and suppression of body weight gains observed at higher doses in the 13-week studies, doses of 0, 100, and 400 mg/kg were used for the 2-year studies in rats and mice. These doses were administered once daily, 5 days a week for up to 103 weeks to groups of 50 males or 50 females of each species. Body Weight and Survival in the 2-Year Studies: The mean body weight of high-dose female rats was 10% to 20% lower than that of controls throughout the studies. Mean body weights for all other dosed rats and for all dosed mice were similar to those of controls throughout the 2-year studies. Survival of high-dose male rats and high-dose and low-dose male mice was significantly lower than that of controls. Survival rates after 2 years were: male rats--control, 37/50; 100 mg/kg, 34/50; 400 mg/kg, 22/50; female rats--24/50; 35/50; 19/50; male mice--38/50; 23/50; 24/50; female mice--32/49; 32/49; 32/50. Neoplasms and Nonneoplastic Lesions in the 2-Year Studies: No chemical-related histopathologic toxic effects or increased incidence of tumors attributable to probenecid were observed in male or female rats receiving probenecid by corn oil gavage for up to 2 years. Mammary gland fibroadenomas and combined thyroid C-cell adenomas or carcinomas exhibited significant negative trends in female rats. These decreased tumor rates were associated with lower body weights. The incidence of adrenal medullary pheochromocytomas was significantly decreased in high-dose male rats. No compound-related increase in nonneoplastic lesions was observed in rats of either sex. No compound-related neoplastic effects were observed in male mice. In high-dose female mice, there were significant increases in the incidences of hepatocellular adenomas (3/48; 2/49; 14/49), but there was no corresponding increase in carcinomas (2/48; 2/49; 3/49). Treatment-related increased incidences of ovarian abscesses in female mice were causally related to Klebsiella species infection rather than directly related to chemical administration. Genetic Toxicology: Probenecid was not mutagenic in Salmonenot mutagenic in Salmonella typhimurium strain TA100, TA1535, TA1537, or TA98 with or without metabolic activation. In cytogenetic tests with Chinese hamster ovary cells, probenecid induced sister chromatid exchanges in the absence, but not in the presence of S9 activation. No induction of chromosomal aberrations was observed with or without S9. Conclusions: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of probenecid for male or female F344/N rats receiving 100 or 400 mg/kg in corn oil. There was no evidence of carcinogenic activity of probenecid for male B6C3F1 mice given 100 or 400 mg/kg probenecid in corn oil. There was some evidence of carcinogenic activity of probenecid for female B6C3F1 mice based on an increased incidence of hepatocellular adenomas. Synonyms: 4-[(Dipropylamino)sulfonyl]benzoic acid; p-(dipropylsulfamoyl)benzoic acid; p-(dipropylsulfamyl)benzoic acid Trade Names: Benacen; Benemid; Benemide; Benn; Probalan; Probecid; Proben; Probenid; Robenecid; Uricocid

Journal Article↗
PubMed1991

NTP Toxicology and Carcinogenesis Studies of Tris(2-chloroethyl) Phosphate (CAS No. 115-96-8) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Tris(2-chloroethyl) phosphate (TRCP), a flame-retardant plasticizer used in plastics, polymeric foams, and synthetic fibers, was studied as part of the National Toxicology Program's class study of trisalkyl phosphate flame retardants. Toxicology and carcinogenesis studies were conducted by administering TRCP (approximately 98% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 16 weeks, or 2 years. Genetic toxicology studies were performed in Salmonella typhimurium and Chinese hamster ovary (CHO) cells. 16-Day Studies: There were no chemical-related deaths, differences in final mean body weight, or histopathological lesions in rats receiving 22 to 350 mg/kg TRCP or in mice receiving 44 to 700 mg/kg TRCP for 12 doses over 16 days. Serum cholinesterase activity in female rats receiving 175 or 350 mg/kg TRCP was reduced slightly (80% of control levels), but enzyme activity in dosed male rats and in mice was similar to that in controls. 16-Week Studies: Rats received 22 to 350 mg/kg TRCP for 16 weeks (female) or 18 weeks (male). Several male and female rats in the 175 or 350 mg/kg dose groups died from chemical toxicity. Final mean body weights of female rats receiving 350 mg/kg were 20% greater than those of controls; final mean body weights of the remaining groups of dosed female rats and dosed male rats were similar. Chemical-related neuronal necrosis occurred in the hippocampus and thalamus of female rats and, to a lesser extent, of male rats. Serum cholinesterase activity was reduced in females receiving 175 or 350 mg/kg TRCP. There were no chemical-related deaths, differences in final mean body weight, or differences in cholinesterase activity in mice receiving 44 to 700 mg/kg TRCP for 16 weeks. Tubule epithelial cells with enlarged nuclei (cytomegaly and karyomegaly) were observed in the kidneys of high-dose (700 mg/kg) male and female mice. 2-Year Studies: The 2-year studies in rats were conducted by administering 0, 44, or 88 mg/kg TRCP to groups of 60 males and females, 5 days per week for up to 104 weeks; 9 or 10 rats of each dose group were evaluated at 66 weeks. The survival of high-dose male and female rats was reduced relative to that of controls. Final mean body weights of surviving rats were similar to those of controls. The principal chemical-related effects occurred in the kidney and brain of dosed rats. Focal hyperplasia of the renal tubule epithelium and renal tubule adenomas were markedly increased in male rats receiving 88 mg/kg TRCP and, to a lesser extent, in female rats (renal tubule hyperplasia, male rats: 0/50; 2/50; 24/50; female rats: 0/50; 3/50; 16/50; renal tubule adenoma, male rats: 1/50; 5/50; 24/50; female rats: 0/50; 2/50; 5/50). Renal tubule carcinomas occurred in one control and one high-dose male rat. Degenerative lesions consisting of gliosis, mineralization, hemorrhage, and/or hemosiderin accumulation occurred in the cerebrum and brain stem of more than 50% of female rats receiving 44 or 88 mg/kg TRCP; similar lesions were seen in only a few dosed males. Slightly increased incidences of thyroid gland follicular cell neoplasms (male rats: 5/50; 14/50; 13/50; female rats: 14/50; 16/50; 20/50) occurred in dosed males and females, but it is uncertain whether these were related to chemical administration. The 2-year studies in mice were conducted by administering 0, 175, or 350 mg/kg TRCP to groups of 60 males and females, 5 days per week for up to 104 weeks; 8 to 10 mice of each sex per dose group were evaluated at 66 weeks. There were no significant differences in survival between dosed and control groups of either sex, and final mean body weights of mice were similar among all groups. The principal chemical-related effects occurred in the kidney, in which nuclear enlargement (karyomegaly) of tubule epithelial cells was present in approximately 80% of high-dose mice. In the original diagnosis, renal tubule adenomas were seen in one control male, one high-dose male, and one low-dose female. A carcinoma was also seen in one high-dose male. In a s seen in one high-dose male. In a subsequent examination of step sections of all the mouse kidneys, adenomas were found in one low-dose male and two high-dose males. The incidences of renal tubule neoplasms in the original and step sections combined were 1/50, 1/50, and 4/50 for males. Female mice receiving TRCP demonstrated a marginally increased incidence of neoplasms (primarily adenomas) of the harderian gland (3/50; 8/50; 7/50); in addition, three harderian gland neoplasms occurred in high-dose female mice evaluated after 66 weeks. Genetic Toxicology: TRCP was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, or TA98 with or without exogenous metabolic activation (S9), and it tested negative for the induction of chromosomal aberrations in Chinese hamster ovary (CHO) cells. TRCP produced an equivocal response in the presence of S9 for the induction of sister chromatid exchanges (SCE) in CHO cells. Conclusions: Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity for male and female F344/N rats receiving tris(2-chloroethyl)phosphate as shown by increased incidences of renal tubule adenomas. Thyroid follicular cell neoplasms and mononuclear cell leukemia in male and female rats may have been related to chemical administration. There was equivocal evidence of carcinogenic activity for male B6C3F1 mice as shown by a marginally increased incidence of renal tubule cell neoplasms. There was equivocal evidence of carcinogenic activity for female B6C3F1 mice as shown by a marginally increased incidence of harderian gland adenomas. Renal tubule cell hyperplasia in male and female rats and gliosis, hemorrhage, pigmentation (hemosiderin accumulation), and mineralization in the brains of female rats were associated with the administration of tris(2-chloroethyl) phosphate. Karyomegaly of renal tubule epithelial cells in male and female mice was also chemical related. Synonyms: 2-chloroethanol phosphate (3:1); tris(b-chloroethyl) phosphate Trade Names: Fyrol CEF; Disflamoll TCA; NIAX flame retardant

Journal Article↗
PubMed1991

NTP Toxicology and Carcinogenesis Studies of 3,3'-Dimethylbenzidine Dihydrochloride (CAS No. 612-82-8) in F344/N Rats (Drinking Water Studies).

3,3'-Dimethylbenzidine dihydrochloride is one of five chemicals being evaluated in 2-year carcinogenicity and toxicity studies as part of the NTP's Benzidine Dye Initiative. This Initiative was designed to evaluate representative benzidine congeners, benzidine congener-derived dyes, and benzidine-derived dyes. 3,3'-Dimethylbenzidine dihydrochloride was nominated for study because of the potential for human exposure during production of bisazobiphenyl dyes and because benzidine, a structurally related chemical, is a known human carcinogen. Toxicology and carcinogenesis studies were conducted by administering 3,3'-dimethylbenzidine dihydrochloride (approximately 99% pure) in drinking water to groups of F344/N rats of each sex for 14 days, 13 weeks, or 9 or 14 months. The 14-month exposures were planned as 24-month exposures but were terminated early because of rapidly declining animal survival, due primarily to neoplasia. These studies were performed only in rats because similar studies were being performed in mice at the National Center for Toxicological Research (NCTR). Hematologic and serum chemical analyses and thyroid hormone determinations were conducted in conjunction with the 13-week and 9-month studies. Genetic toxicology studies were conducted in Salmonella typhimurium, Chinese hamster ovary (CHO) cells, and Drosophila melanogaster. 14-Day Studies: Rats were exposed to 3,3'-dimethylbenzidine dihydrochloride in drinking water at doses ranging from 600 to 7,500 ppm. All five males and one female in the 7,500 ppm group and 1/5 males in the 5,000 ppm group died. Final mean body weights were decreased in males receiving 1,250 ppm or more and in all exposed females, and final mean body weights of animals receiving 2,500 ppm or more were lower than initial weights. Water consumption decreased with increasing chemical concentration. Compound-related effects observed in rats receiving 5,000 ppm or more included minimal to slight hepatocellular necrosis, accumulation of brown pigment (presumably bile) in individual hepatocytes, increased severity of nephropathy relative to controls, and severe lymphocytic atrophy of the thymus. Treated animals also showed an increased severity of atrophy of the bone marrow relative to controls, varying degrees of lymphocytic atrophy of the mandibular and mesenteric lymph nodes and spleen, increased vacuolization and necrosis of cells of the adrenal cortex, focal acinar cell degeneration in the pancreas, and, in males, increased immature sperm forms in the testis and epididymis. 13-Week Studies: 3,3'-Dimethylbenzidine dihydrochloride was administered in drinking water at doses of 300, 500, 1,000, 2,000, and 4,000 ppm. All rats receiving 4,000 ppm and 4/10 males and 1/10 females receiving 2,000 ppm died before the end of the studies. Depressions in final mean body weight relative to controls ranged from 12% to 48% for males and from 9% to 42% for females. Water consumption decreased with increasing dose. At compound concentrations of 300 to 2,000 ppm, mean water consumption was 29% to 83% of control values. Compound-related effects included an increase in the severity of nephropathy relative to controls; hepatocellular necrosis and accumulation of brown pigment (presumably bile) in sinusoidal lining cells; lymphocytic atrophy of the thymus, spleen, and mandibular and mesenteric lymph nodes; atrophy of the bone marrow in the higher-dose groups; degeneration of pancreatic acinar cells; and, in males, immature sperm forms in the testis and epididymis. Decreases in serum triiodothyronine (T3) values were observed in exposed females, and decreases in mean thyroxin (T4) concentrations in exposed males and females; no significant changes were observed in thyroid stimulating hormone (TSH) levels in exposed rats. Based on the decreased survival, reductions in water consumption and body weight gain, and chemical-induced hepatocellular and renal lesions observed in the 13-week studies, the doses selected for the 9- and 14-month drinking water studies of 3,3'-dimethylbenzidine dihydrochloride were 0, 3 3,3'-dimethylbenzidine dihydrochloride were 0, 30, 70, and 150 ppm. Seventy rats of each sex were used in the control group, 45 in the low-dose group, 75 in the mid-dose group, and 70 in the high-dose group. 9-Month Studies: Ten rats of each sex in the control and 150 ppm dose groups were evaluated after 9 months. Chemical-related effects observed in exposed animals included alveolar/bronchiolar carcinoma in one male, basal cell carcinoma of the skin in one male, a squamous cell carcinoma of the oral cavity in one female, preputial gland carcinoma in two males, clitoral gland carcinoma in three females, adenocarcinoma of the small intestine in two males, Zymbal's gland carcinoma in two males and three females, hepatocellular carcinoma in two males, and adenomatous polyps of the large intestine in three males. Other effects seen in dosed rats included focal cellular alteration in the liver, lymphoid atrophy in the spleen, and increased severity of nephropathy relative to controls. An increase in serum T3 values was observed in exposed males, and a decrease in mean T4 concentrations in exposed males and females. TSH concentrations were increased in exposed male and female rats. Body Weights and Survival in the 14-Month Studies: The average amount of 3,3'-dimethylbenzidine dihydrochloride consumed per day was approximately 1.8, 4.0, or 11.2, mg/kg for low-, mid-, or high-dose male rats and 3.0, 6.9, or 12.9 mg/kg for low-, mid-, or high-dose female rats. The mean body weight of high-dose males was about 85% of the control value by week 28. By the end of the study, mean body weights of low-, mid-, and high-dose males were 97%, 92%, and 70% of the control values, respectively. Mean body weights of high- and mid-dose females were about 85% of the control values at week 32 and week 44, respectively. At the end of the study, mean body weights of exposed females were about 94%, 81%, and 74% of the control values for low-, mid-, and high-dose groups, respectively. Because of extensive neoplasia, many exposed males and females were dying or were sacrificed moribund in the first year, and all high-dose males died by week 55. The studies were terminated at weeks 60 to 61, at which time the group survivals were male: control, 60/60, low dose, 41/45; mid dose, 50/75; high dose, 0/60; female: 59/60; 39/45; 32/75; 10/60. Nonneoplastic Effects in the 14-Month Studies: Increases in nonneoplastic lesions in dosed rats included cystic degeneration and foci of cellular alteration in the liver; exacerbation of nephropathy; and focal or multifocal hyperplasia of the Zymbal's gland, preputial and clitoral glands, and alveolar epithelium. Neoplastic Effects in the 14-Month Studies: Neoplasms were observed in exposed rats at many sites: skin, Zymbal's gland, preputial and clitoral glands, liver, oral cavity, small and large intestine, mammary gland, lung, brain, and mesothelium. The incidence of these neoplastic effects in male and female rats is summarized in the table at the end of this section (see page 8 of the Technical Report). Genetic Toxicology: 3,3'-Dimethylbenzidine dihydrochloride was mutagenic in Salmonella typhimurium strain TA98 with exogenous metabolic activation; it was not mutagenic in strains TA100, TA1535, or TA97 with or without activation. 3,3'-Dimethylbenzidine dihydrochloride induced sister-chromatid exchanges (CHO) and chromosomal aberrations in CHO cells in the absence of exogenous metabolic activation; these effects were not evident in test with S9 activation. Sex-linked recessive lethal mutations were induced in germ cells of adult male Drosophila melanogaster administered 3,3'-dimethylbenzidine dihydrochloride in feed or by injection. No reciprocal translocations occurred in D. melanogaster germ cells following exposure to 3,3'-dimethylbenzidine dihydrochloride. Conclusions: Under the conditions of these 14-month drinking water studies, there was clear evidence of carcinogenic activity of 3,3'-dimethylbenzidine dihydrochloride for male F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, preputial gland, liver, oral cavity, small and large intestine, lung, and mesothelium. Increased incidences of neoplasms of the brain may have been related to chemical administration. There was clear evidence of carcinogenic activity for female F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, clitoral gland, liver, oral cavity, small and large intestine, mammary gland, and lung. Increased incidences of neoplasms of the brain and mononuclear cell leukemia may have been related to chemical administration. Synonyms: o-tolidine dihydrochloride; 3,3'-dimethylbiphenyl-4,4'-diamine dihydrochloride; 3,3'-dimethylbiphenyl-4,4'-biphenyldiamine dihydrochloride; 4,4'-diamino-3,3'-dimethylbiphenyl dihydrochloride

Journal Article↗
PubMed1991

NTP Toxicology and Carcinogeneis Studies of Sodium Azide (CAS: 26628-22-8) in F344 Rats (Gavage Studies).

Sodium azide is a white crystalline solid used in the manufacture of the explosive lead azide. It is the principal chemical used to generate nitrogen gas in automobile safety airbags and airplane escape chutes and is a broad-spectrum biocide used in both research and agriculture. Toxicology and carcinogenicity studies were conducted by administering sodium azide (greater than 99% pure) in distilled water by gavage to groups of male and female F344/N rats once daily, 5 days per week for 14 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Chinese hamster ovary cells. 14-Day Studies: Rats received 0, 5, 10, 20, 40, or 80 mg/kg sodium azide. All male and female rats receiving 40 or 80 mg/kg and two of five female rats receiving 20 mg/kg died during the first week of the studies. Clinical findings of toxicity included lethargy and inactivity. No grossly observable lesions were present in any of the dose groups. 13-Week Studies: Rats received 0, 1.25, 2.5, 5, 10, or 20 mg/kg sodium azide. Seven of 9 males and all 10 females receiving 20 mg/kg died before the end of the studies. Final mean body weights of treated rats were within 10% of those of the controls. Compound-related clinical findings of toxicity in the 20 mg/kg dose groups included lethargy and labored breathing. Histopathologic lesions induced by sodium azide were limited to the brain (necrosis of the cerebrum and thalamus) and lung (congestion, hemorrhage, and edema), and were observed in rats receiving 20 mg/kg that died during the studies. Body Weights, Feed Consumption, and Survival in the 2-Year Studies: Because compound-related deaths were observed in the groups receiving 20 mg/kg in the 13-week studies, lower dose levels were used in the 2-year studies. Two-year studies were conducted by administering 0, 5, or 10 mg/kg sodium azide to groups of 60 male and 60 female rats. Dose-related depression in mean body weight was observed throughout the study period. Mean feed consumption values in low- and high-dose groups were lower than control values. Survival of high-dose rats of each sex was significantly (P<0.05) lower than controls (males-control, 24/60; low-dose, 27/60; high-dose, 9/60; females-37/60; 43/60; 21/59). The reduced survival was attributed to brain necrosis and cardiovascular collapse induced by sodium azide. Neoplastic and Nonneoplastic Effects in the 2-Year Studies: There were no compound-related increases in incidences of neoplasms in rats. Significantly decreased incidences were observed for certain neoplasms, including mononuclear cell leukemia in male rats (control, 33/60; low-dose, 28/60; high-dose, 14/60), adrenal gland pheochromocytoma in male rats (26/55; 16/56; 6/54), mammary gland fibroadenoma in female rats (20/60; 11/60; 8/59), and pituitary gland neoplasms in female rats (37/60; 28/60; 17/59). These decreases reflected to some extent, but could not be attributed solely to, the reduced survival of the high-dose groups. Compound-related nonneoplastic brain lesions (necrosis of the cerebrum and thalamus) were observed at significantly (P<0.001) increased incidences in high-dose male and female rats. The increased incidence of lung congestion observed in this dose group was considered due to cardiovascular collapse secondary to brain necrosis. Genetic Toxicology: Sodium azide was mutagenic in Salmonella typhimurium strains TA100 and TA1535, with or without exogenous metabolic activation (S9); it was not mutagenic in strain TA1537 or TA98. In cytogenetic tests with Chinese hamster ovary cells, sodium azide induced sister chromatid exchanges, but not chromosomal aberrations, in the presence and the absence of S9. Conclusions: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of sodium azide in male or female F344/N rats administered 5 or 10 mg/kg. Sodium azide induced necrosis in the cerebrum and the thalamus of the brain in both male and female rats. Synonyms: Azide, Azium, Smite

Journal Article↗
PubMed1991

NTP Toxicology and Carcinogenesis Studies of dl-Amphetamine Sulfate (CAS No. 60-13-9) in F344/N Rats and B6C3F1 Mice (Feed Studies).

dl-Amphetamine sulfate is used for the treatment of narcolepsy in adults and behavioral syndromes in children. Toxicology and carcinogenesis studies were conducted by administering dl-amphetamine sulfate (USP grade) in feed to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Chinese hamster ovary (CHO) cells. 14-Day Studies: The chemical was administered at dietary concentrations of 0, 47, 94, 188, 375, or 750 ppm for rats and 0, 125, 250, 500, 1,000, or 2,000 ppm for mice. Decreased body weight gain was seen at the higher concentrations, but no chemical-related deaths or toxic lesions were observed. 13-Week Studies: The chemical was administered at dietary concentrations of 0, 47, 94, 188, 375, or 750 ppm for rats and 0, 125, 250, 500, 1,000, or 2,000 ppm for mice. None of the rats died, but 6/10 male mice and 7/10 female mice that received 2,000 ppm, 3/10 male mice that received 1,000 ppm, and 8/10 male mice that received 500 ppm died before the end of the studies. Decreased body weight gain and hyperactivity were seen in dosed rats and mice. Final body weights of rats receiving 188 ppm or more were 62% to 89% those of controls, and final body weights of mice receiving 250 ppm or more were 70% to 86% those of controls. There were no lesions that were considered to be a primary effect of the chemical. Based on decreased body weight gain and hyperactivity in the 13-week studies, 2-year studies were conducted by feeding diets containing 0, 20 or 100 ppm dl-amphetamine sulfate to groups of 50 rats or 50 mice of each sex. Body Weights and Survival in the 2-Year Studies: No significant differences in survival were observed between any groups of rats or mice (male rats: control, 30/50; low dose, 31/50; high dose, 33/50; female rats: 33/50; 42/50; 37/50; male mice: 48/50; 48/50; 49/50; female mice: 35/50; 36/50; 44/50). Final body weights of dosed rats and mice were decreased relative to those of controls. Final body weights were 92% and 86% those of controls for low- and high-dose male rats, 89% and 70% those of controls for low- and high-dose female rats, 85% and 72% those of controls for low- and high-dose male mice, and 81% and 66% those of controls for low- and high-dose female mice. Hyperactivity was observed in all dosed groups. Feed consumption was similar among control and exposed groups with the exception of high-dose female rats (84% of controls) and high-dose male mice, for which hyperactivity resulted in scattering of feed and overestimation of feed consumption. The average amount of dl-amphetamine sulfate consumed per day was estimated to be 1 or 5 mg/kg for low- and high-dose rats, 4 or 30 mg/kg for low- or high-dose male mice, and 3 or 19 mg/kg for low- or high-dose female mice. Nonneoplastic and Neoplastic Effects in the 2-Year Studies: Myelofibrosis, cataracts, and retinal atrophy in female rats, and ovarian atrophy in female mice occurred in a larger proportion of high-dose animals than in controls. Dose-related increases in neoplasms did not occur in rats or mice receiving amphetamine. The administration of dl-amphetamine sulfate was associated with decreases in the incidence of total neoplasms and in the incidences of certain site-specific neoplasms, including pheochromocytomas of the adrenal gland in male rats (23/49, 15/44, 7/50), fibroadenomas of the mammary gland in female rats (21/50, 11/50, 2/50), adenomas of the anterior pituitary gland in male and female rats and female mice (male rats: 15/49, 15/48, 9/49; female rats: 31/50, 24/48, 19/50; female mice: 12/49, 6/49, 1/46), endometrial stromal polyps of the uterus of female rats (10/50, 6/50, 3/50), adenomas or carcinomas (combined) of the liver in male and female mice (male: 14/50, 12/50, 2/50; female: 5/50, 1/50, 1/47), adenomas of the harderian gland in male and female mice (male: 4/50, 2/50, 0/50; female: 5/50, 2/50, 0/47), and adenomas or carcinomas (combined) of the lung in male and female mice (male: 8/50, 3/50, 4/50; female: 8/50, 6/50 (combined) of the lung in male and female mice (male: 8/50, 3/50, 4/50; female: 8/50, 6/50, 1/47). Genetic Toxicology: dl-Amphetamine sulfate was tested for induction of gene mutations in Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 with and without exogenous metabolic activation (S9); the only response observed was in strain TA98 in the presence of S9, and it was judged to be equivocal. No induction of sister chromatid exchanges or chromosomal aberrations occurred in Chinese hamster ovary cells treated with amphetamine sulfate in either the presence or the absence of S9. Conclusions: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of dl-amphetamine sulfate for male or female F344/N rats or male or female B6C3F1 mice fed 20 or 100 ppm. The administration of dl-amphetamine sulfate was associated with decreased body weight. There were decreased incidences of total neoplasms in dosed rats and mice, of adrenal pheochromocytomas in male rats, of mammary gland fibroadenomas and uterine polyps in female rats, of pituitary gland adenomas in male and female rats and female mice, and of harderian gland adenomas, liver neoplasms, and lung neoplasms in male and female mice. Synonyms: (&plusmn;)-amphetamine sulfate; (&plusmn;)-2-amino-1-phenylpropane sulfate; amphetamine sulfate; deoxynorephedrine; desoxynorephedrine; (&plusmn;)-a-methylphenethylamine sulfate; (&plusmn;)-phenisopropylamine sulfate; b-phenyl isopropylamine Trade Names: Acedron; Adipan; Adiparthrol; Aketdrin; Aktedrin; Alentol; Amfetamina; Amphaetamin; Amphamed; Amphatamin; Amphate; Amphedrine; Amphetaminum; Amphezamin; Amphoids-S; Anara; Anfetamina; Anorexine; Astedin; Benzafinyl; Benzamphetamine; Benzebar; Benzedrina; Benzedryna; Benzolone; Benzpropamine;Betafen; Betaphen; Bluzedrin; Centramina; Didrex; Dietamine; Durophet; Elastonin; Elastonon; Euphobine; Euphodine; Euphodyn; Fabedrine; Fenamin; Fenara; Fenedrin; Fenopromin; Halloo-Wach; Ibiozedrine; Isamin; Isoamin; Isoamyne; Isomyn; Leodrin; Levonor; Linampheta; Mecodrin; Mimetina; Monetamine; Noclon; Norephedrane; Norphedrane; Novydrine; Oktedrin; Oraldrina; Ortenal; Orthedrin; Percomon; Pharmamedrine; Pharmedrine; Phenamine; Phenedrine; Phenopromin; Phenpromin; Profamina; Profetamine; Propenyl; Propisamine; Psychedrine; Psychedryna; Psychedrinum; Psychoton; Racephen; Rhinalator; Sedolin; Simpamina; Simpamine; Simpatedrin; Stimulan; Sympametin; Sympamine; Sympatedrine; Synsatedrine; Theptine; Vapedrine; Weckamine; Zedrine Slang for Amphetamines: bennies; benzies; cartwheels; hearts; peaches; roses

Journal Article↗
PubMed1990

NTP Toxicology and Carcinogenesis Studies of Sodium Fluoride (CAS No. 7681-49-4)in F344/N Rats and B6C3F1 Mice (Drinking Water Studies).

Sodium fluoride is a white, crystalline, water-soluble powder used in municipal water fluoridation systems, in various dental products, and in a variety of industrial applications. Toxicology and carcinogenesis studies were conducted with F344/N rats and B6C3F1 mice of each sex by incorporating sodium fluoride into the drinking water in studies lasting 14 days, 6 months, and 2 years. In addition, genetic toxicology studies were performed with Salmonella typhimurium, with mouse L5178Y cells, and with Chinese hamster ovary cells. 14-Day Studies: Rats and mice received sodium fluoride in drinking water at concentrations as high as 800 ppm. (Concentrations are expressed as sodium fluoride; fluoride ion is 45% of the sodium salt by weight.) In the high-dose groups, 5/5 male and 5/5 female rats and 2/5 male mice died; one female rat was given 400 ppm in the drinking water also died before the end of the studies. No gross lesions were attributed to sodium fluoride administration. 6-Month Studies: Rats received concentrations of sodium fluoride in drinking water as high as 300 ppm, and mice as high as 600 ppm. No rats died during the studies; however, among the mice, 4/9 high-dose males, 9/11 high-dose females, and 1/8 males in the 300 ppm group died before the end of the studies. Weight gains were less than those of controls for rats receiving 300 ppm and mice receiving 200 to 600 ppm. The teeth of rats and mice receiving the higher doses of sodium fluoride were chalky white and chipped or showed unusual wear patterns. Mice and male rats given the higher concentrations had microscopic focal degeneration of the enamel organ. Rats receiving 100 or 300 ppm sodium fluoride had minimal hyperplasia of the gastric mucosa of the stomach, and one high-dose rat of each sex had an ulcer. Acute nephrosis and/or lesions in the liver and myocardium were observed in mice that died early, and minimal alterations in bone growth/remodeling were observed in the long bones of mice receiving sodium fluoride at concentrations of 50 to 600 ppm. The sodium fluoride concentrations selected for the 2-year studies in both rats and mice were 0, 25, 100, and 175 ppm in the drinking water. These concentrations were selected based on the decreased weight gain of rats at 300 ppm and of mice at 200 ppm and above, on the incidence of gastric lesions in rats at 300 ppm in the 6-month studies, and on the absence of significant toxic effects at sodium fluoride concentrations as high as 100 ppm in an earlier 2-year study. Body Weights and Survival in the 2-Year Studies: Mean body weights of dosed and control groups of rats and mice were similar throughout the 2-year studies. Survival of rats and mice was not affected by sodium fluoride administration. Survival rates after 2 years were: male rats-control, 42/80; 25 ppm, 25/51; 100 ppm, 23/50; 175 ppm, 42/80; female rats-59/80; 31/50; 34/50; 54/81; male mice-58/79; 39/50; 37/51; 65/80; female mice-53/80; 38/52; 34/50; 52/80. Neoplastic and Nonneoplastic Effects in the 2-Year Studies: The teeth of rats and mice has a dose-dependent whitish discoloration, and male rats had an increased incidence of tooth deformities and attrition leading on occasion to malocclusion. The teeth of male and, to a lesser degree, female rats had areas of microscopic dentine dysplasia and degeneration of ameloblasts. Dentine dysplasia occurred in both dosed and control groups of male and female mice; the incidence of this lesion was significantly greater in high-dose than in control male mice. Osteosclerosis of long bones was increased in female rats given drinking water containing 175 ppm sodium fluoride. No other significant nonneoplastic lesions in rats or mice appeared related to sodium fluoride administration. Osteosarcomas of bone were observed in 1/50 male rats in the 100 ppm group and in 3/80 male rats in the 175 ppm group. None were seen in the control or 25 ppm dose groups. One other 175 ppm male rat had an extraskeletal osteosarcoma arising in the subcutaneous tissue. Osteosarcomas occur in historical control male rats at an incian incidence of 0.5&percnt; (range 0-6&percnt;). The historical incidence is not directly comparable with the incidences observed in this study because examination of bone was more comprehensive in the sodium fluoride studies than in previous NTP studies of other chemicals, and the diet used in previous studies was not controlled for fluoride content. In the current study, although the pairwise comparison of the incidence in the 175 ppm group versus that in the controls was not statistically significant, osteosarcomas occurred with a statistically significant dose-response trend, leading to the conclusion that a weak association may exist between the occurrence of these neoplasms and the administration of sodium fluoride. No other neoplastic lesions in rats or mice were considered possibly related to chemical administration. Genetic Toxicology: Sodium fluoride was negative for gene mutation induction in Salmonella typhimurium strains TA100, TA1535, TA1537, and TA98 with and without S9. In two laboratories, sodium fluoride was tested for induction of trifluorothymidine resistance in mouse L5178Y lymphoma cells; results were positive both with and without S9. Sodium fluoride was tested for cytogenetic effects in Chinese hamster ovary (CHO) cells in two laboratories. In the first laboratory, the sister chromatid exchange (SCE) test was negative with and without S9, and the chromosomal aberration (Abs) test was positive in the absence of S9; in the second laboratory, the SCE test was positive with and without S9, but no induction of Abs was observed. The laboratory that reported a negative result for Abs tested at doses below that shown to be positive at the other laboratory. Similarly, the positive SCE result was obtained at a higher dose and longer harvest time than used by the laboratory reporting the negative SCE response. Conclusions: Under the conditions of these 2-year dosed water studies, there was equivocal evidence of carcinogenic activity of sodium fluoride in male F344/N rats, based on the occurrence of a small number of osteosarcomas in dosed animals. "Equivocal evidence" is a category for uncertain findings defined as studies that are interpreted as showing a marginal increase of neoplasms that may be related to chemical administration. There was no evidence of carcinogenic activity in female F344/N rats receiving sodium fluoride at concentrations of 25, 100, or 175 ppm (11, 45, or 79 ppm fluoride) in drinking water for 2 years. There was no evidence of carcinogenic activity of sodium fluoride in male or female mice receiving sodium fluoride at concentrations of 25, 100, or 175 ppm in drinking water for 2 years. Dosed rats had lesions typical of fluorosis of the teeth and female rats receiving drinking water containing 175 ppm sodium fluoride had increased osteosclerosis of long bones.

Journal Article↗
PubMed1990

NTP Toxicology and Carcinogenesis Studies of Tetranitromethane (CAS No. 509-14-8) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

Tetranitromethane is a volatile contaminant formed during the manufacture of TNT and has been used as a rocket fuel and biochemical reagent. Toxicology and carcinogenesis studies were conducted in F344/N rats and B6C3F1 mice of each sex by whole body exposure to tetranitromethane vapor (greater than 99% pure), 6 hours per day, 5 days per week for 14 days, 13 weeks, or 2 years. Additional groups of male mice were exposed to tetranitromethane for evaluation at 1 year. Genetic toxicology studies were performed in Salmonella typhimurium and Chinese hamster ovary (CHO) cells. Fourteen-Day Studies: Exposure concentrations ranged from 2 to 25 ppm for rats and from 2 to 50 ppm for mice. All rats exposed to 25 ppm and all mice exposed at the top concentration of 50 ppm died by day 2; reduced survival was seen in mice exposed to 25 ppm and in rats exposed to 10 ppm. Pulmonary edema in rats and inflammation of the lung in mice were seen in those animals in the 25- and 50-ppm exposure groups examined microscopically. Thirteen-Week Studies: Exposure concentrations ranged from 0.2 to 10 ppm for rats and mice. No exposure-related deaths occurred in rats. The final mean body weight of rats exposed to 10 ppm was 16% lower than that of controls for males and 6% lower for females. Exposure-related histologic effects included squamous metaplasia of the respiratory epithelium of the nasal mucosa and chronic inflammation of the lung. No deaths of mice could be clearly related to exposure to tetranitromethane. The final mean body weights of mice exposed to 5 or 10 ppm were 5% or 12% lower than that of controls for males and 9% or 12% lower for females. Exposure-related histologic effects in mice included inflammation and squamous metaplasia of the respiratory epithelium of the nasal mucosa and hyperplasia of the bronchiolar epithelium. Based on the incidences and severity of lesions in the respiratory at the higher concentrations used in the 13-week studies, exposure concentrations chosen for the 2-year studies were 0, 2, and 5 ppm for groups of 50 rats of each sex and 0, 0.5, and 2 ppm for groups of 50 mice of each sex. Additional groups of 6 or 10 male mice were exposed at concentrations of 0, 0.5, or 2 ppm for 1 year. Body Weights and Survival in the Two-Year Studies: Mean body weights of male and female rats exposed to 5 ppm were approximately 5%-15% lower than those of controls after week 70. Survival of rats at 104 weeks was as follows: male: control, 18/50; 2 ppm, 17/50; 5 ppm, 4/50; female: 25/50; 34/50; 15/50; survival of rats at the top concentration was reduced due to neoplasia. Mean body weights of exposed mice were variable and ranged as much as 10% below those of controls during the second year of the studies. Survival of exposed male mice at 104 weeks was significantly lower than that of controls due to neoplasia (control, 37/50; 0.5 ppm, 26/50; 2 ppm, 15/50). Survival of female mice was not significantly affected by exposure to tetranitromethane (31/50; 28/50; 24/50). Neoplastic and Nonneoplastic Effects in the Two-Year Studies: Effects of exposure to tetranitromethane were limited to the respiratory tract. Hyperplasia of the alveolar and bronchiolar epithelium was observed at increased incidences in exposed rats. The incidence of alveolar/bronchiolar adenomas and carcinomas were markedly increased in exposed male and female rats, with carcinomas (many of which metastasized to other sites) occurring in nearly all rats exposed to the top concentration of 5 ppm (adenomas or carcinomas-- male: control, 1/50; 2 ppm, 33/50; 5 ppm, 46/50; female: 0/50; 22/50; 50/50). Many of the rats exposed to 5 ppm also had squamous cell carcinomas of the lung (male: 0/50; 1/50; 19/50; female: 0/50; 1/50; 12/50). Hyperplasia of the respiratory epithelium and chronic inflammation of the nasal mucosa were observed at increased incidences in exposed male and female rats. Squamous metaplasia of the respiratory epithelium was increased in exposed male rats. No neoplasms of the nasal passage were seen. In exposed mice, hyperplasia of the alveolar and br were seen. In exposed mice, hyperplasia of the alveolar and bronchiolar epithelium was observed at increased incidences. Alveolar/bronchiolar neoplasms, primarily carcinomas (many of which metastasized to other sites), were increased in exposed male and female mice (male: control, 12/50; 0.5 ppm, 27/50; 2 ppm, 47/50; female: 4/49; 24/50; 49/50). Chronic inflammation of the nasal mucosa and hyperplasia and squamous metaplasia of the respiratory epithelium of the nasal cavity occurred at increased incidences in female mice exposed to 2 ppm. No primary neoplasms of the nasal passage were observed in mice. Oncogene Analysis: DNA from 14/19 rat and 4/4 mouse lung neoplasms caused morphologic transformation after transfection into cultured NIH/3T3 fibroblasts. The transforming gene from both rat and mouse lung neoplasms was determined by Southern blot analysis to be an activated K-ras oncogene. Further studies showed a GC-->AT transition in the second base of the 12th codon of the K-ras oncogene. Genetic Toxicology: Tetranitromethane was mutagenic in S. typhimurium strains TA98, TA100, and TA1535 with and without exogenous metabolic activation (S9); no mutagenic activity was observed in TA1537 with or without S9. Chromosomal aberrations were observed in CHO cells treated in vitro with tetranitromethane in the presence of S9. Sister chromatid exchanges were induced in CHO cells in the absence of S9. Conclusions: Under the conditions of these 2-year inhalation studies, there was clear evidence of carcinogenic activity of tetranitromethane for male and female F344/N rats and male and female B6C3F1 mice, based on increased incidences of alveolar/bronchiolar neoplasms in both species and squamous cell carcinomas of the lung in rats. Chronic inflammation of the nasal mucosa was related to exposure in rats and female mice, and hyperplasia and squamous metaplasia of the respiratory epithelium were increased in exposed male rats. Synonym: TNM

Journal Article↗
PubMed1990

NTP Toxicology and Carcinogenesis Studies of a-Methylbenzyl Alcohol (CAS No. 98-85-1) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

NTP Toxicology and Carcinogenesis studies of a-methylbenzyl alcohol (greater than 99% pure), a cosmetic ingredient and food flavoring agent, were conducted by administering the chemical in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse lymphoma cells, and Chinese hamster ovary (CHO) cells. a-Methylbenzyl alcohol was nominated for study by the National Cancer Institute because of the potential for widespread human exposure. Sixteen-Day and Thirteen-Week Studies: The doses used in the 16-day studies for rats and mice ranged between 125 and 2,000 mg/kg. Six of 10 rats and all mice dosed at 2,000 mg/kg died. In addition, because 7/9 mice dosed at 1,000 mg/kg died, the doses selected for the 13-week studies for mice (47-750 mg/kg) were half those used for rats (93-1,500 mg/kg). In the 13-week studies, deaths of 1/10 male and 3/10 female rats dosed at 1,500 mg/kg were compound related; none of the mice died. Body weight gain was reduced in rats at 1,500 mg/kg; there were no significant histopathologic lesions in either rats or mice. The only compound-related effects were ataxia, labored breathing, and lethargy for up to 30 minutes after dosing in rats and mice given the two highest doses and increases in liver weight to body weight ratios for male rats given the three highest doses and for female rats at all doses. Based on the pattern of mortality and the effects on body weight gain in the short-term studies, doses of 375 and 750 mg/kg a-methylbenzyl alcohol were administered in corn oil by gavage, 5 days per week for 103 weeks, to groups of 50 rats and 50 mice of each sex. Two-Year Studies: Significant reduction in body weight gain commenced at weeks 20-30 in high dose male and female rats, and body weights were 20%-30% below those of vehicle controls at study termination. In the low dose groups, body weight reduction occurred only in male rats during the last 10 weeks of the study. After 80 weeks, 60% of the high dose rats and 80%-100% of the low dose and vehicle control rats were alive; thereafter, the number of deaths in the chemically exposed groups increased sharply so that, at the end of 2 years, final survival for vehicle control, low dose, and high dose rats was 35/50; 8/50; and 1/50 for males and 34/50, 25/50, and 11/50 for females. There were a large number of gavage accidents in these studies (1, 9, and 8 for male rats and 1, 4, and 14 for female rats), but these accidents did not contribute to the increase in mortality after week 80, as all but 4 of these occurred earlier. Mortality in the last quarter of the study was thought to be due to the effects of cumulative toxicity of a-methylbenzyl alcohol on a renal excretory system already compromised by aging. Renal nephropathy that commonly occurs during aging was found in all groups of rats, but the severity was greater in male rats dosed with a-methylbenzyl alcohol. In addition, a collection of nonneoplastic lesions (parathyroid hyperplasia, calcification of the heart and glandular stomach, and fibrous osteodystrophy of bone) was found in the dosed male rats; these lesions were probably secondary to mineral imbalance arising from renal dysfunction. Since survival was poor in low and high dose male and high dose female rats, the sensitivity of the study for detecting a carcinogenic effect in these groups was reduced. Despite this limitation, there were dose-related increases in the incidences of renal tubular cell adenomas or adenocarcinomas (combined) in male rats (vehicle control, 0/50; low dose, 2/50; high dose, 5/50). In addition, transitional cell papillomas of the urinary bladder were observed in one high dose male and two high dose female rats. In mice, a reduction in body weight gain was apparent in the high dose groups of males and females. Final survival rates in mice were similar among groups (male: 39/49; 40/50; 28/50; female: 41/50; 41/50; 38/50). No neoplastic or nonneoplastic lesions were attributed to a-methylbenzyl lesions were attributed to a-methylbenzyl alcohol administration in mice of either sex. Genetic Toxicology: a-Methylbenzyl alcohol was not mutagenic in S. typhimurium strains TA98, TA100, TA1535, or TA1537 when tested in the presence or absence of exogenous metabolic activation. a-Methylbenzyl alcohol produced a positive response without activation in the mouse L5178Y/TK+/- lymphoma assay for induction of trifluorothymidine resistance; it was not tested with activation. In cytogenetic tests with CHO cells, a-methylbenzyl alcohol induced chromosomal aberrations in the presence, but not the absence, of metabolic activation; no induction of sister chromatid exchanges was observed in CHO cells after exposure to a-methylbenzyl alcohol. Conclusions: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activityof a-methylbenzyl alcohol for male F344/N rats, as shown by increased incidences of renal tubular cell adenomas and adenomas or adenocarcinomas (combined). There was no evidence of carcinogenic activity for female F344/N rats administered 375 or 750 mg/kg. Renal toxicity characterized by severe nephropathy and related secondary lesions was observed in the dosed rats, and excessive mortality occurred during the last quarter of the studies. Poor survival reduced the sensitivity of the studies for detecting the presence of a carcinogenic response both in chemically exposed groups of male rats and in the high dose group of female rats. There was no evidence of carcinogenic activity of a-methylbenzyl alcohol for male or female B6C3F1 mice administered 375 or 750 mg/kg for 2 years. Synonyms: styrallyl alcohol; styralyl alcohol; a-methylbenzenemethanol; phenylmethylcarbinol; 1-phenethyl alcohol

Journal Article↗
PubMed1990

NTP Toxicology and Carcinogenesis Studies of Phenylbutazone (CAS No. 50-33-9) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Phenylbutazone is a nonsteroidal anti-inflammatory drug. NTP Toxicology and Carcinogenesis studies were conducted by administering phenylbutazone (greater than 99% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 19 days, 13 weeks, or 2 years. Genetic toxicology studies were performed with Salmonella typhimurium, mouse L5178Y lymphoma cells, and Chinese hamster ovary (CHO) cells. Nineteen-Day Studies: The deaths of 3/5 male and 4/5 female rats that received 600 mg/kg and of 2/5 females that received 300 mg/kg were considered to be chemically related. The final mean body weight of rats that received 300 or 600 mg/kg was 14%-15% or 46% lower than that of vehicle controls. No compound-related deaths occurred in mice (doses up to 600 mg/kg). The final mean body weights of dosed and vehicle control mice were similar. Thirteen-Week Studies: Most rats that received 300 mg/kg and 1/10 male and 2/10 female rats that received 200 mg/kg died early. The final mean body weight of male rats at 300 mg/kg was 31% lower than that of the vehicle controls. The liver weight to body weight ratios were increased in the 200 and 300 mg/kg group of rats. Compound-related lesions occurred mainly in the kidney and included papillary necrosis, papillary edema, and multifocal mineralization. Five of 10 male mice and 4/10 female mice that received 600 mg/kg died early. No other compound-related deaths occurred in mice. Final mean body weights of dosed and vehicle control mice were comparable. The liver weight to body weight ratios were increased for mice at 300 and 600 mg/kg. No compound-related histopathologic effects were observed in mice. Body Weight and Survival in the Two-Year Studies: Two-year studies were conducted by administering 0, 50, or 100 mg/kg phenylbutazone in corn oil by gavage to groups of 50 rats of each sex, 5 days per week for 103 weeks. The doses given groups of 50 mice of each sex on the same schedule were 0, 150, or 300 mg/kg. Mean body weights of high dose rats were generally 6%-11% lower than those of vehicle controls. Mean body weights of mice were similar among all groups except for high dose female mice, which weighed 4%-11% less than vehicle controls. The survival of all groups was similar except for that of the low dose group of male rats, which was significantly lower than that of the vehicle controls at the end of the studies; the survival of the top dose group of female rats and the vehicle control group of female mice was low but not statistically reduced(final survival--male rats: vehicle control, 33/50; low dose, 20/50; high dose, 27/50; female rats: 31/50; 35/50; 22/50; male mice: 36/50; 40/50; female mice: 22/50; 29/50; 32/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Mild pyelonephritis, renal papillary necrosis, and mineralization of the renal papillae in dosed male and female rats and hyperplasia of the renal pelvis epithelium, dilatation of the renal pelvis, and renal cysts in dosed female rats were observed at increased incidences compared with those in vehicle controls. A renal tubular cell carcinoma was observed in one low dose male rat, and renal tubular adenomas were observed in three high dose male rats. A carcinoma of uncertain histogenesis was observed in one low dose female rat. Carcinomas of the renal transitional epithelium were seen in two high dose female rats. When the kidneys were step-sectioned, additional tubular cell adenomas were diagnosed in four low dose and one high dose male rats and in three low dose and one high dose female rats; none was observed in vehicle controls. Papillomas of the transitional epithelium of the urinary bladder were seen in 2/43 low dose male and 1/49 low dose female F344/N rats. The historical incidence of urinary bladder transitional cell neoplasms in male corn oil vehicle control F344/N rats is 5/2,034 (0.2%; highest observed incidence, 2/50) and 4/2,026 (0.2%; highest observed incidence, 1/45) in females. Adrenal medullary hyperplasia was observed at an increased incidence in high dose female rats (veherplasia was observed at an increased incidence in high dose female rats (vehicle control, 3/50; low dose, 6/50; high dose, 19/50). Ulcers of the forestomach were observed at increased incidences in high dose rats (male: 0/50; 5/50; 6/50; female: 2/49; 1/49; 12/49). In high dose female rats, acanthosis (4/49; 0/49; 12/49), hyperkeratosis (3/49; 0/49; 12/49), and basal cell hyperplasia (4/49; 1/49; 12/49) of the forestomach were observed at increased incidences. No neoplasms were associated with these stomach lesions. Peliosis hepatis, centrilobular cytomegaly and karyomegaly, fatty change, hepatocellular degeneration, and coagulative necrosis of the liver were observed in dosed male mice; clear cell foci were observed in five high dose male mice. The incidences of hepatocellular adenomas and adenomas or carcinomas (combined) in male mice were increased in the high dose group (adenomas or carcinomas, combined: 16/50; 14/50; 31/50). Genetic Toxicology: Phenylbutazone was not mutagenic in S. typhimurium strains TA98, TA100, TA1535, or TA1537 when tested with or without exogenous metabolic activation. Phenylbutazone produced a positive response in the mouse lymphoma assay in both the presence and absence of activation. Phenylbutazone induced chromosomal aberrations in CHO cells in the presence, but not the absence, of exogenous metabolic activation; no induction of sister chromatid exchanges was observed in CHO cells in the presence or absence of activation. Conclusions: Under the conditions of these 2-year gavage studies, there was equivocal evidence of carcinogenic activity of phenylbutazone for male F344/N rats, as shown by the occurrence of small numbers of renal tubular cell adenomas or carcinomas. There was some evidence of carcinogenic activity for female F344/N rats, as shown primarily by the occurrence of two rare transitional cell carcinomas in the top dose group; none has ever been seen in vehicle control or untreated control female rats. Tubular cell adenomas may have been associated with the administration of phenylbutazone to female rats. There was some evidence of carcinogenic activity for male B6C3F1 mice, as shown by the increased incidence of hepatocellular adenomas or carcinomas (combined). There was no evidence of carcinogenicity for female B6C3F1 mice administered phenylbutazone in corn oil by gavage at doses of 150 or 300 mg/kg. Phenylbutazone was also nephrotoxic to rats, as shown by the dose-related increase in the severity of age-related nephropathy, necrosis of the renal papilla, and mineralization of the collecting ducts in the papilla. Synonyms: 4-butyl-1,2-diphenyl-3,5-pyrazolidinedione; 3,5-dioxo-1,2-diphenyl-4-n-butylpyrazolidine Trade Names: There have been over 100 registered trade names including: Anerval; Azobutil; Bizolin 200; Butacote; Butadion; Butagesic; Butazolidin; Chembutazone; Equi Bute; Flexazone; Fenibutol; G 13,871; Pyrazolidin; Reumazol; Robizon-V; Uzone

Journal Article↗
PubMed1990

NTP Toxicology and Carcinogenesis Studies of l-Epinephrine Hydrochloride (CAS No. 55-31-2) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

l-Epinephrine, an endogenous neurotransmitter hormone, is widely used for the treatment of allergic and respiratory disorders. NTP Toxicology and Carcinogenesis studies of epinephrine hydrochloride were conducted by exposing groups of F344/N rats and B6C3F1 mice of each sex to an aerosol containing epinephrine hydrochloride for 14 days, 13 weeks, 15 months, or 2 years. During the 14-day and 13-week studies, control animals were exposed to dilute aerosols of hydrochloric acid (pH 2.8), whereas during the 15-month and 2-year studies, controls were exposed to aerosols of water. Genetic toxicology studies of epinephrine were conducted in Salmonella typhimurium and Chinese hamster ovary (CHO) cells. Fourteen-Day Studies: Rats and mice were exposed to 0 or 12.5-200 mg/m3 epinephrine hydrochloride. Deaths occurred in male rats exposed to 12.5 mg/m3 or more and in females exposed to 25 mg/m3 or more. Deaths of mice occurred at concentrations of 50 mg/m3 or higher. Compound-related clinical signs included an increased respiratory rate in all groups of epinephrine-exposed rats and mice. At higher concentrations (100 and 200 mg/m3), excessive lacrimation and dyspnea in rats and exaggerated visual and auditory reflexes in mice were observed. Thirteen-Week Studies: Rats and mice were exposed to 0 or 2.5-40 mg/m3 epinephrine hydrochloride. Deaths in rats and mice were not concentration related. Final mean body weights of chemically exposed and hydrochloric acid aerosol control rats and mice were generally similar. Increased respiratory rates were noted in rats and mice exposed to 40 mg/m3. Heart and adrenal gland weights of rats and mice and liver weights of mice exposed to 40 mg/m3 were greater than those of aerosol controls. Squamous metaplasia occurred in the respiratory epithelium of the nasal mucosa of rats and mice exposed to 40 mg/m3. Degenerative lesions of the laryngeal muscle were seen in male and female rats exposed to 20 or 40 mg/m3. Inflammation in the glandular stomach was seen in male and female mice exposed to 10, 20, and 40 mg/m3, and uterine atrophy was seen in 7/10 female mice exposed to 40 mg/m3. Two-year studies were conducted by exposing groups of 60 rats or each sex to 0, 1.5, or 5 mg/m3 epinephrine hydrochloride, 5 days per week for 103 weeks. Groups of 60 mice of each sex were exposed to 0, 1.5, or 3 mg/m3 epinephrine hydrochloride, 5 days per week for 104 weeks. Use of these exposure concentrations represented a departure from the usual practice of utilizing doses equivalent to one-half the maximum tolerated dose (MTD) and the MTD for 2-year carcinogenicity studies. Thus, although the dose levels exceeded maximum human therapeutic use levels (normalized to body weight and surface area), they were less than one-half the MTD. Fifteen-Month Studies: Results of hematologic analyses did not show compound-related changes. Absolute liver weights for exposed mice (3 mg/m3) and rats (5 mg/m3) and relative liver weights for exposed rats (5 mg/m3) were significantly lower than those for controls. The absolute kidney weights for mice exposed to 3 mg/m3 and the kidney weight to body weight ratio for male mice exposed to 3 mg/m3 were significantly lower than those for controls. No compound-related lesions were seen in rats or mice. Body Weights and Survival in the Two-Year Studies: Mean body weights and survival of exposed and control rats and mice were similar (survival, rats--male: control, 33/50; 1.5 mg/m3, 27/50; 5 mg/m3, 32/50; female: 32/50; 29/50; 30/50; mice--male: control, 33/50; 1.5 mg/m3, 34/50; 3 mg/m3, 36/50; female: 32/50; 35/50; 34/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Suppurative inflammation of the nasal mucosa, dilatation of the nasal glands (Bowman's and septal), and hyperplasia of the respiratory epithelium were seen at increased incidences in male rats exposed to 5 mg/m3 and in female rats exposed to 1.5 or 5 mg/m3. Hyaline degeneration of the olfactory epithelium in male mice and suppurative inflammation of the nasal passage and hyaline degeneration of the respiratory epithelium in female mice were increased in the 1.5 and 3 mg/m3 groups compared with controls. No neoplasms seen in these studies were considered related to chemical exposure. Genetic Toxicology: Salmonella gene mutation tests with l-epinephrine yielded negative results in strain TA100 in the presence of exogenous metabolic activation (S9) and equivocal results in the absence of S9. No mutagenic activity was observed in strains TA98, TA1535, or TA1537 with or without S9. The responses observed in the CHO cell assay for induction of sister chromatid exchanges were considered to be negative and equivocal in the presence and absence of S9 activation, respectively. l-Epinephrine did not induce chromosomal aberrations in CHO cells with or without S9. Conclusions: Under the conditions of these 2-year studies, no carcinogenic effects were observed in male or female F344/N rats exposed to aerosols containing 1.5 or 5 mg/m3 l-epinephrine hydrochloride for 2 years or in B6C3F1 mice exposed to 1.5 or 3 mg/m3 l-epinephrine hydrochloride for 2 years. However, these studies were considered to be inadequate studies of carcinogenic activity because the concentrations used, which were chosen to represent multiples of therapeutic doses, were considered too low for the animals to have received an adequate systemic challenge from the compound. Synonyms: adrenaline hydrochloride; 4-(1-hydroxy-2-(methylamino)ethyl)-1,2-benzenediol; (-)3,4-dihydroxy-a-((methylamino)methyl)benzyl alcohol hydrochloride; methylaminoethanol catechol hydrochloride Trade names for epinephrine formulations: Primatene&reg;. Mist; Sus-Phrine&reg;.; Epipen&reg;.; Supravenin Hydrochloride&reg;.; Bronkaid&reg;.

Journal Article↗
PubMed1990

NTP Toxicology and Carcinogenesis Studies of 2-Chloroacetophenone (CAS No. 532-27-4) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

2-Chloroacetophenone is a potent lacrimator that has been used as a riot control agent and in tear gas formulations for personal protection devices. NTP Toxicology and Carcinogenesis studies were conducted by exposing groups of F344/N rats and B6C3F1 mice of each sex to air containing 2-chloroacetophenone vapor for 14 days, 13 weeks, 15 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Chinese hamster ovary (CHO) cells. Fourteen-Day Studies: In 14-day studies, exposure concentrations of 2-chloroacetophenone ranged from 4.8 to 64 mg/m3. All rats exposed to 19, 43, or 64 mg/m3 died during the first week of the studies and 1/5 male rats exposed to 10 mg/m3 died during the second week of the study. Rats exposed to 10 mg/m3 lost weight; the final mean body weights of male or female rats exposed to 4.8 mg/m3, the lowest concentration used, were 23% or 15% lower than that of controls. During the exposure, rats showed partial closure of the eyelids, excessive lacrimation (dacryorrhea), dyspnea, and erythema. All mice exposed to 10 mg/m3 or higher concentrations of 2-chloroacetophenone died during the first week of the studies. The final mean body weights of mice exposed to 4.8 mg/m3 were similar to those of controls. Dacryorrhea was observed in exposed mice. Thirteen-Week Studies: The exposure concentrations of 2-chloroacetophenone ranged from 0.25 to 4 mg/m3 for rats and mice. All rats lived to the end of the studies. The final mean body weights of rats exposed to 4 mg/m3 were 9% lower than those of controls. Eye irritation during exposure was evident in rats exposed to 0.5 mg/m3 or higher concentrations of 2-chloroacetophenone. One of 10 female mice exposed to 4 mg/m3 and 1/10 female mice exposed to 0.5 mg/m3 died before the end of the study. The final mean body weights of exposed mice were 7%-12% lower than that of controls for males and 12%-15% lower for females. No chemical-related gross or microscopic lesions were observed in rats or mice. In the 2-year studies, groups of 60 rats of each sex were exposed to a vapor of 0 (chamber control), 1, or 2 mg/m3 (0, 0.15, or 0.3 ppm) 2-chloroacetophenone, 6 hours per day, 5 days per week. Groups of 60 mice of each sex were exposed to 0 (chamber control), 2, or 4 mg/m3 (0, 0.3, or 0.6 ppm) on the same schedule. Ten animals from each group were killed and examined at 15 months; the remaining animals continued on study for 2 years. Fifteen-Month Studies: In the 15-month studies, minimal-to-mild focal squamous metaplasia and hyperplasia of the respiratory epithelium were seen at increased incidences in rats exposed to 2 mg/m3. No exposure-related lesions were observed in mice of either sex. Body Weight and Survival in the Two-Year Studies: Mean body weights and survival of exposed and chamber control rats were similar throughout most of the studies (survival-male: control, 14/50; 1 mg/m3, 22/50; 2 mg/m3, 17/50; female: 23/50; 20/50; 24/50). Mean body weights of male mice exposed to 4 mg/m3 were about 5%-12% lower than those of controls after week 30; small differences between mean body weights of exposed and control female mice were not clearly exposure related. The survival of female mice exposed to 2 mg/m3 was significantly lower than that of chamber controls after week 98. No other differences in survival were observed between any groups of mice (male: control, 34/50; 2 mg/m3, 36/50; 4 mg/m3, 33/50; female: 40/50; 28/50; 32/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Fibroadenomas of the mammary gland occurred in female rats with positive trends, and the incidence in the 2 mg/m3 group was greater than that in chamber controls (control, 12/50; 1 mg/m3, 19/50; 2 mg/m3, 23/50). The incidences of adenomas or adenocarcinomas of the mammary gland were not increased in the exposed groups. Minimal-to-mild suppurative inflammation of the nasal mucosa was observed at increased incidences in exposed male rats. Hyperplasia and squamous metaplasia of the nasal respiratory epithelium were observed at increased incidences in exposed ry epithelium were observed at increased incidences in exposed male and female rats. In mice, squamous metaplasia of the respiratory epithelium of the nasal passage was seen in four females and two males exposed to 4 mg/m3 2-chloroacetophenone. Inflammation, ulcers, and squamous hyperplasia of the forestomach were observed at increased incidences in exposed female rats. Genetic Toxicology: 2-Chloroacetophenone was not mutagenic in S. typhimurium strains TA98, TA100, TA1535, or TA1537 with or without exogenous metabolic activation. In cytogenetic tests with CHO cells, 2-chloroacetophenone did not induce sister chromatid exchanges with or without activation, but a weak positive increase in chromosomal aberrations was observed in the absence of metabolic activation. Conclusions: Under the conditions of these 2-year inhalation studies, there was no evidence of carcinogenic activity of 2-chloroacetophenone for male rats exposed to 1 or 2 mg/m3. There was equivocal evidence of carcinogenic activity for female F344/N rats, based on a marginal increase in fibroadenomas of the mammary gland. There was no evidence of carcinogenic activity for male or female B6C3F1 mice exposed to 2 or 4 mg/m3 2-chloroacetophenone. Synonyms: a-chloroacetophenone; 2-chloro-1-phenylethanone; CN; phenacyl chloride; phenylchloromethylketone Trade Names: Mace&reg;.; Chemical Mace&reg;.

Journal Article↗
PubMed1990

NTP Toxicology and Carcinogenesis Studies of Benzaldehyde (CAS No. 100-52-7) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Benzaldehyde is an aromatic aldehyde used in the food, beverage, pharmaceutical, perfume, soap, and dyestuff industries. NTP Toxicology and Carcinogenesis studies were conducted by administering benzaldehyde (99% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse lymphoma cells, Chinese hamster ovary (CHO) cells, and Drosophila melanogaster. Sixteen-Day Studies: All rats that received 1,600 mg/kg died by day 2, and 2/5 males and 2/5 females that received 800 mg/kg died before the end of the studies. Final mean body weights of dosed and vehicle control rats were similar, with the exception of the 800 mg/kg groups, in which males were 14% lighter and females were 11% lighter than vehicle controls. All mice that received 1,600 or 3,200 mg/kg died by day 3. Final mean body weights of dosed and vehicle control mice were similar. No gross lesions attributable to benzaldehyde were detected upon necropsy. Thirteen-Week Studies: Six of 10 male rats and 3/10 female rats that received 800 mg/kg and 1/10 female rats that received 400 mg/kg died near the end of the studies. Final mean body weights of dosed and vehicle control rats were similar, with the exception of male rats receiving 800 mg/kg, which were 26% lighter than vehicle controls. Compound-related lesions seen in rats receiving 800 mg/kg, but not in those receiving 400 mg/kg, included degeneration and necrosis in the cerebellum, necrosis in the hippocampus, hyperplasia and/or hyperkeratosis in the forestomach, and degeneration or necrosis of the liver and of the tubular epithelium in the kidney. Nine of 10 male mice and 1/10 female mice that received 1,200 mg/kg benzaldehyde died by the end of the first week. Compound-related renal tubule degeneration and/or necrosis and reduction in final body weight were observed in the 600 mg/kg group of male mice. No reductions in body weight or compound-related lesions were seen in female mice. Based on observations of compound-related lesions involving the brain, forestomach, kidney, and liver of male and female rats and the kidney of male mice in the 13-week studies, 2-year studies were conducted by administering 0, 200, or 400 mg/kg benzaldehyde in corn oil by gavage, 5 days per week for 103 weeks to groups of 50 male and 50 female rats and for 104 weeks to groups of 50 male mice. Based on survival data from the 16-day and 13-week studies, groups of 50 female mice were administered 0, 300, or 600 mg/kg benzaldehyde for 103 weeks. Body Weights and Survival in the Two-Year Studies: Mean body weights of dosed rats and mice were similar to their respective vehicle controls throughout the studies. The survival of the high dose group of male rats was lower than that of the vehicle controls after 1 year; no other significant differences were observed between any groups of rats or mice (survival--male rats; vehicle control, 37/50; low dose, 29/50; high dose, 21/50; female rats: 33/50; 33/50; 29/50; male mice: 32/50; 33/50; 31/50, female mice: 30/50; 27/50; 35/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: The only effects of benzaldehyde were those seen in the forestomach of mice. The incidences of uncommonly occurring squamous cell papillomas of the forestomach in both exposure groups were significantly greater than those in vehicle controls (male: vehicle control, 1/50; low dose, 2/50; high dose, 5/50; female: 0/50; 5/50; 6/50). The increased incidences of papillomas were accompanied by dose-related increases in the incidences in forestomach hyperplasia (male: 7/50; 8/50; 16/50; female: 12/50; 23/50; 39/50). Genetic Toxicology: Benzaldehyde was not mutagenic in six strains of S. typhimurium and did not induce chromosomal aberrations in CHO cells, with or without exogenous metabolic activation. Benzaldehyde induced increases in trifluorothymidine-resistant mouse lymphoma cells in the absence exogenous metabolic activation and increased sister chromatid exchanges in CHO cells in boexchanges in CHO cells in both the presence and absence of metabolic activation. Sex-linked recessive lethal mutations were not induced in the germ cells of adult male D. melanogaster administered benzaldehyde by feeding or by injection. Conclusions: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of benzaldehyde for male or female F344/N rats receiving 200 or 400 mg/kg per day. There was some evidence of carcinogenic activity of benzaldehyde for male or female B6C3F1 mice, as indicated by increased incidences of squamous cell papillomas and hyperplasia of the forestomach. Female rats and male and female mice might have been able to tolerate higher doses. Synonyms: artificial almond oil; artificial essential oil of almond; benzenecarbonal; benzene carbaldehyde; benzoic aldehyde; phenylmethanal

Journal Article↗
PubMed1990

NTP Toxicology and Carcinogenesis Studies of CS2 (94% o-Chlorobenzalmalononitrile, CAS No. 2698-41-1) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

CS2 (94% o-chlorobenzalmalononitrile [CS]; 5% Cab-O-Sil(R). colloidal silica; 1% hexamethyldisilizane), an eye and respiratory irritant, is used as an aerosol to control riots. NTP Toxicology and Carcinogenesis studies were conducted by exposing groups of F344/N rats and B6C3F1 mice of each sex for 6 hours per day, 5 days per week for 2 weeks, 13 weeks, or 2 years, to a CS2 aerosol. Genetic toxicology studies with CS2 were conducted in Salmonella typhimurium, mouse lymphoma cells, and Chinese hamster ovary (CHO) cells. Fourteen-Day Studies: At exposure concentrations of 0, 1, 3, 10, 30, or 100 mg/m3 CS2, all rats exposed to 30 or 100 mg/m3 and all mice exposed to 10, 30, or 100 mg/m3 died before the end of the studies. Compound-related clinical signs observed included erythema, blepharospasm, listlessness, nasal discharge, and mouse breathing. Thirteen-Week Studies: At exposure concentrations of 0, 0.4, 0.75, 1.5, 3, or 6 mg/m3, 1/10 male rats exposed to 6 mg/m3 died before the end of the studies. Final mean body weights of rats exposed to 1.5 mg/m3 or more were 17%-44% lower than that of controls for males and 10%-24% lower for females. The absolute and relative thymus weights were reduced for exposed male and female rats, particularly at 6 mg/m3. Compound-related lesions of the nasal passage in rats included focal erosion with regenerative hyperplasia and squamous metaplasia of the respiratory epithelium and suppurative inflammation. Acute inflammation and hyperplasia of the respiratory epithelium were seen in the larynx and trachea of some exposed rats. All mice exposed to 6 mg/m3 and 1/10 males and 1/10 females exposed to 3 mg/m3 died before the end of the studies. Final mean body weights of mice exposed to 3 mg/m3 were 13% lower than that of controls for males and 9% lower for females. Compound-related lesions of the nasal passage in mice included squamous metaplasia of the nasal respiratory epithelium and inflammation. Based on these results, CS2 exposure concentrations for the 2-year studies were 0, 0.075, 0.25, or 0.75 mg/m3 for 6 hours per day, 5 days per week for 105 weeks for groups of 50 rats of each sex. Groups of 50 mice of each sex were exposed to 0, 0.75, or 1.5 mg/m3 on the same schedule. Body Weights and Survival in the Two-Year Studies: Final mean body weights of rats exposed to 0.75 mg/m3 were 7%-11% lower than those of controls. Final mean body weights of mice exposed to CS2 were lower than those of controls (male: 5% and 9%; female: 10% and 17%). No compound-related clinical signs were observed. No significant differences in survival were seen for any group of rats or mice of either sex. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Compound-related nonneoplastic lesions occurred in the nasal passage of exposed rats and mice. In exposed rats, hyperplasia and squamous metaplasia of the respiratory epithelium and degeneration of the olfactory epithelium with ciliated columnar and/or squamous metaplasia were observed. Focal chronic inflammation and proliferation of the periosteum of the turbinate bones were increased slightly in rats at the top exposure concentration. Suppurative inflammation with hyperplasia and squamous metaplasia of the respiratory epithelium occurred in exposed mice. There were no compound-related increased incidences of neoplasms in rats or mice exposed to CS2. In exposed female mice, there were pronounced decreases in the incidences of adenomas of the pituitary pars distalis (control, 13/47; 0.75 mg/m3, 5/46; 1.5 mg/m3, 1/46) and decreased incidences of malignant lymphomas (21/50; 12/50; 8/50). Genetic Toxicology: The responses in Salmonella gene mutation tests with CS2 were equivocal in one laboratory for strain TA100 in the absence of exogenous metabolic activation (S9) and equivocal in another laboratory for TA97 with S9; in all other strains tested, CS2 was clearly negative with or without S9. CS2 induced trifluorothymidine resistance in mouse L5178Y/TK lymphoma cells in the absence of S9; it was not tested with S9. CS2 induced both sister chromatid exchangeslymphoma cells in the absence of S9; it was not tested with S9. CS2 induced both sister chromatid exchanges and chromosomal aberrations in CHO cells with and without S9. Conclusions: Under the conditions of these inhalation studies, there was no evidence of carcinogenic activity of CS2 for male or female F344/N rats exposed to 0.075, 0.25, or 0.75 mg/m3 in air for up to 2 years. There was no evidence of carcinogenic activity for male or female B6C3F1 mice exposed to 0.75 or 1.5 mg/m3 in air for up to 2 years. Concentration-related decreases in the incidences of pituitary gland adenomas and lymphomas were observed in female mice. Exposure to CS2 caused degeneration and squamous metaplasia of the olfactory epithelium, hyperplasia and metaplasia of the respiratory epithelium, and proliferation of the periosteum of the nasal passage of rats. In mice, exposure to this compound caused suppurative inflammation and hyperplasia and squamous metaplasia of the respiratory epithelium of the nasal passage.

Journal Article↗
PubMed1990

NTP Toxicology and Carcinogenesis Studies of Allyl Glycidyl Ether (CAS No. 106-92-3) in Osborne-Mendel Rats and B6C3F1 Mice (Inhalation Studies).

Allyl glycidyl ether is used as a resin intermediate and as a stabilizer of chlorinated compounds, vinyl resins, and rubber. NTP Toxicology and Carcinogenesis studies were conducted by exposing groups of Osborne-Mendel rats and B6C3F1 of each sex to allyl gylcidyl ether (greater than 97% pure) by inhalation for 6 hours per day, 5 days per week for 2 weeks, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Chinese hamster ovary (CHO) cells, and Drosophila melanogaster. Studies of reproductive effects were conducted in rats and mice exposed to allyl glycidyl ether for 8 weeks. Two-Week Studies: Exposure concentrations ranged up to 500 ppm in rats and 100 ppm in mice. All rats that were exposed to 500 ppm died; no deaths occurred at the next lower (200 ppm) exposure concentration. All male mice and 3/5 female mice exposed to 100 ppm and 2/5 male mice and 1/5 female mice exposed to 50 ppm died. Compound-related lesions in rats and mice included acute inflammation of the nasal passage and major airways. Eight-Week Studies of Reproductive Effects: Rats were exposed to 0-200 ppm allyl glycidyl ether, and mice were exposed to 0-30 ppm, 6 hours per day, 5 days per week for 8 weeks. The mating performance of exposed male rats was markedly reduced; however, sperm motility and number were not affected. No deficiencies were seen in the reproductive performance of exposed female rats or male or female mice. Thirteen-Week Studies: Exposure concentrations ranged up to 200 ppm for rats and 30 ppm for mice. All rats lived to the end of the studies. The final mean body weights of male rats exposed to 10-200 ppm were 7%-24% lower than that of controls. Clinical signs attributable to irritation of the upper respiratory tract and eyes were seen in exposed animals. Histologic lesions included squamous metaplasia of the nasal passage in all exposure groups (4 ppm, lowest concentration) and involved both the respiratory epithelium and the olfactory epithelium. The lesions were more severe anteriorly and dorsally and with increasing concentration. At 30 ppm and higher, erosion was seen in the nasal passage and squamous metaplasia was seen in the upper airways. There were no compound-related deaths in mice. The final mean body weights of mice exposed to 30 ppm were 12% lower than those of controls for both males and females. Mice exposed to 10 or 30 ppm allyl glycidyl ether had squamous metaplasia of the nasal passage, involving both the respiratory epithelium and the olfactory epithelium, which tended to be more severe in the anterior and dorsal portions of the nasal passage. In mice exposed to 30 ppm, epithelial erosions were also found. Body Weights and Survival in the Two-Year Studies: Two-year studies were conducted by exposing groups of 50 Osborne-Mendel rats and B6C3F1 mice of each sex to 0, 5, or 10 ppm allyl glycidyl ether by inhalation for 6 hours per day, 5 days per week for 102 or 103 weeks. Mean body weights of the exposed rats were within 8% of those of controls throughout the studies. Mean body weights of mice exposed to 5 or 10 ppm were 5%-20% lower than those of controls. Deaths were seen in all groups of male rats beginning at 1 year of age (final survival-- control, 12/50; 5 ppm, 11/50; 10 ppm, 8/50). Survival of female rats was not exposure related (24/50; 30/50; 25/50). Exposed mice had slightly increased survival (male mice: 38/50; 39/50; 46/50; female mice: 33/50; 42/50; 41/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: In male rats exposed to 10 ppm allyl glycidyl ether, three apparently unrelated neoplasms of the nasal passage were found. Two neoplasms, a papillary adenoma and a squamous cell carcinoma, appeared to arise from different cell types in the respiratory epithelium. One poorly differentiated adenocarcinoma in the olfactory region was also found. One papillary adenoma of respiratory epithelial origin was found in a female rat exposed to 5 ppm. Exposure-related nonneoplastic lesions of the nasal passages in rats included inflammation, squamous metaplasiin rats included inflammation, squamous metaplasia, respiratory metaplasia (replacement of olfactory epithelium by ciliated epithelium), hyperplasia of the respiratory epithelium, and degeneration of the olfactory epithelium. In male mice exposed to 10 ppm allyl glycidyl ether, a hemangioma and three papillary adenomas were present in the nasal passage. In female mice exposed to 10 ppm, a hemangioma and an adenoma were found in the nasal passage. Nonneoplastic lesions of the nasal passages in mice included inflammation, squamous metaplasia, hyperplasia, basal cell hyperplasia, dysplasia of the respiratory epithelium, and metaplasia of the olfactory epithelium. In male mice, there was an exposure-related decrease in the incidences of hepatocellular neoplasms; in female mice, there was a decrease in the incidences of pituitary gland adenomas. Genetic Toxicology: Allyl glycidyl ether was mutagenic in S. typhimurium strains TA100 and TA1535 with and without exogenous metabolic activation; no mutagenic activity was observed in strains TA98 or TA1537. Allyl glycidyl ether induced sister chromatid exchanges and chromosomal aberrations in CHO cells both in the presence and the absence of metabolic activation. A significant increase in sex-linked recessive lethal mutations was recorded in the germ cells of male D. melanogaster fed a sucrose solution containing allyl glycidyl ether, but no increase in reciprocal translocations occurred in these cells. Conclusions: Under the conditions of these 2-year inhalation studies, there was equivocal evidence of carcinogenic activity of allyl glycidyl ether for male Osborne-Mendel rats, based on the presence of one papillary adenoma of respiratory epithelial origin, one squamous cell carcinoma of respiratory epithelial origin, and one poorly differentiated adenocarcinoma of olfactory epithelial origin, all occurring in the nasal passage of males exposed to 10 ppm. There was no evidence of carcinogenic activity of allyl glycidyl ether for female rats. One papillary adenoma of the respiratory epithelium was present in a female rat exposed to 5 ppm. There was some evidence of carcinogenic activity of allyl glycidyl ether for male B6C3F1 mice, based on the presence of three adenomas of the respiratory epithelium, dysplasia in four males, and focal basal cell hyperplasia of the respiratory epithelium in seven males in the nasal passage of mice exposed to 10 ppm. There was equivocal evidence of carcinogenic activity of allyl glycidyl ether for female mice, based on the presence of one adenoma of the respiratory epithelium and focal basal cell hyperplasia of the respiratory epithelium in seven females exposed to 10 ppm. The sensitivity of the assay to detect potential carcinogenicity may have been reduced in male rats because of poor survival in all groups. In exposed mice, body weights were decreased 10&percnt; or more, mortality was decreased, and there were lower incidences of liver neoplasms (males) and pituitary gland adenomas (females) compared with controls. Significant exposure-related nonneoplastic lesions were restricted to the nasal passage in both rats and mice and induced inflammation, metaplasia, respiratory epithelial hyperplasia, and olfactory epithelial degeneration. Basal cell hyperplasia and dysplasia of the respiratory epithelium of the nasal passage were found only in the mice. Synonyms: allyl 2,3-epoxypropyl ether; 1-allyloxy-2,3-epoxypropane; 1,2-epoxy-3-allyloxypropane; glycidyl allyl ether; ((2-propenyloxy)methyl)oxirane; 1-(allyloxy)-2,3-epoxypropane

Journal Article↗
PubMed1990

NTP Toxicology and Carcinogenesis Studies of Vinyl Toluene (Mixed Isomers) (65%-71% meta-isomer and 32-35% para-isomer) (CAS No. 25013-15-4) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

Vinyl Toluene is used as a monomer in the plastics and surface-coating industries. NTP Toxicology and Carcinogenesis studies were conducted by exposing groups of F344/N rats and B6C3F1 mice of each sex to vinyl toluene (mixed isomers: 65%-71% meta and 32%-35% para) by inhalation 6 hours per day, 5 days per week, for 15 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse L5178Y cells, and Chinese hamster ovary (CHO) cells. Fifteen-Day Studies: Rats were exposed to 0, 200, 400, 800, or 1,300 ppm vinyl toluene, and mice were exposed to 0, 10, 25, 50, 100, or 200 ppm. All rats lived to the end of the studies. The mean body weights at necropsy of rats exposed to 400-1,300 ppm were 13%-19% lower than that of controls for males and 9%-13% lower for females. Most male rats exposed to 1,300 ppm had centrilobular necrosis and focal inflammatory cell infiltration of the liver, whereas minimal centrilobular vacuolization of the liver was seen in all female rats exposed to 1,300 ppm. Dysplasia of the bronchial epithelial lining, chronic bronchitis, and lymphoid hyperplasia of the lung were observed in all rats exposed to 1,300 ppm. Three of five male mice exposed to 200 ppm vinyl toluene died before the end of the studies. Four of five male mice exposed to 200 ppm had moderate-to-severe hepatocellular necrosis; all female mice exposed to 200 ppm had hyperplasia of the epithelium of the intrapulmonary bronchi and centrilobular necrosis, vacuolization, and inflammatory cell infiltrates in the liver. Thirteen-Week Studies: Rats were exposed to 0, 25, 60, 160, 400, or 1,000 ppm vinyl toluene. All rats lived to the end of the studies. The final mean body weights of rats exposed to 400-1,000 ppm were 8%-19% lower than that of controls for males and 6%-12% lower for females. Relative liver weights for rats at 1,000 ppm were significantly greater than those for controls. The severity of nephropathy was increased in male rats exposed to 160, 400, or 1,000 ppm. Compound-related lesions were not observed in female rats. Mice were exposed to 0, 10, 25, 60, or 160 ppm vinyl toluene. The final mean body weights of mice exposed to 25-160 ppm were 12%-20% lower than that of controls for males and 13%-16% lower for females. Inflammation of the lung was observed in 5/10 male and 3/9 female mice exposed to 160 ppm. Metaplasia of the nasal turbinates was seen in all exposed groups. Based on these results, 2-year studies were conducted by exposing groups of 49 or 50 rats of each sex to 0, 100, or 300 ppm vinyl toluene by inhalation, 6 hours per day, 5 days per week for 103 weeks. Groups of 50 mice of each sex were exposed to 0, 10, or 25 ppm on the same schedule. Body Weights and Survival in the Two-Year Studies: Mean body weights of male rats exposed to 300 ppm vinyl toluene and those of female rats exposed to 100 and 300 ppm were generally 4%-11% lower than those of controls. No significant differences in survival were seen between any groups of rats of either sex (male: control, 19/49; low dose, 17/50; high dose, 19/50; female: 31/50; 28/50; 26/50). Mean body weights of mice exposed to 25 ppm were 10%-23% lower than those of controls after week 8, whereas mice exposed to 10 ppm showed a weight decrement that was generally less than 10%. The survival of male mice exposed to 25 ppm was significantly greater than that of controls. No other significant differences in survival were seen between any groups of mice of either sex (male: 33/50; 30/50; 41/50; female: 36/50; 37/50; 34/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Degenerative and nonneoplastic proliferative lesions of the nasal mucosa were observed at increased incidences in exposed rats. These lesions included diffuse hyperplasia (goblet cell) of the respiratory epithelium with intraepithelial mucous cysts and focal erosion of the olfactory epithelium with cystic dilation (cysts) of the Bowman's glands. Focal respiratory epithelial metaplasia of the olfactory epithelium was seen in some exposed males, and cells with homoge) of the Bowman's glands. Focal respiratory epithelial metaplasia of the olfactory epithelium was seen in some exposed males, and cells with homogeneous eosinophilic cytoplasm in the olfactory epithelium occurred at increased incidences in exposed female rats. Neoplasms of the nasal mucosa were not seen in male or female rats. There were no chemically related increases in neoplasm incidence in exposed male or female rats. Degenerative and inflammatory lesions of the nasal mucosa were observed at increased incidences in exposed mice. These lesions included focal chronic active inflammation and diffuse hyperplasia of the respiratory epithelium. Chronic active inflammation of the bronchioles occurred in many exposed mice but not in controls. Neoplasms of the nasal passage were not observed in mice. There were no chemically related increases in neoplasm incidence in exposed male or female mice. Exposure-related decreased incidences included alveolar/bronchiolar neoplasms (control, 12/50; 10 ppm, 5/49; 25 ppm, 2/49) and malignant lymphomas (7/50; 3/50; 0/50) in males and hepatocellular neoplasms (9/48; 5/16; 2/49) in females. Genetic Toxicology: Vinyl toluene did not induce gene mutations in S. typhimurium strains TA98, TA100, TA1535, or TA1537 with or without exogenous metabolic activation (S9). Vinyl toluene was positive in the mouse lymphoma assay for induction of trifluorothymidine resistance in L5178Y/TK cells in the absence of S9; it was not tested with S9. Vinyl toluene did not induce sister chromatid exchanges or chromosomal aberrations in CHO cells with or without S9. Conclusions: Under the conditions of these 2-year inhalation studies, there was no evidence of carcinogenic activity for male or female F344/N rats exposed to 100 or 300 ppm vinyl toluene and no evidence of carcinogenic activity for male or female B6C3F1 mice exposed to 10 or 25 ppm. There was evidence of chemical-related toxicity to the nasal passage in both rats and mice. Synonyms: 3-vinyl toluene and 4-vinyl toluene (mixed isomers)

Journal Article↗
PubMed1990

NTP Toxicology and Carcinogenesis Studies of Glycidol (CAS No. 556-52-5) In F344/N Rats and B6C3F1 Mice (Gavage Studies).

Glycidol is a viscous liquid that is used as a stabilizer in the manufacture of vinyl polymers, as an additive for oil and synthetic hydraulic fluids, and as a diluent in some epoxy resins. NTP Toxicology and Carcinogenesis studies were conducted by administering glycidol (94% pure, containing 1.2% 3-methoxy-1,2-propanediol, 0.4% 3-chloro-1,2-propanediol, 2.8% diglycidyl ether, and 1.1% 2,6-dimethanol-1,4-dioxane) in water by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Chinese hamster ovary (CHO) cells, Drosophila melanogaster, and the bone marrow of male B6C3F1 mice. Sixteen-Day Studies: Glycidol doses for groups of five rats or five mice of each sex ranged from 37.5 to 600 mg/kg; vehicle controls received distilled water. All rats that received 600 mg/kg died between days 3 and 13. Edema and degeneration of the epididymal stroma, atrophy of the testis, and granulomatous inflammation of the epididymis occurred in males that received 300 mg/kg. All mice that received 600 mg/kg and two males and two females that received 300 mg/kg died by day 4 of the studies. Focal demyelination in the medulla and thalamus of the brain occurred in all female mice that received 300 mg/kg. Thirteen-Week Studies: Doses for groups of 10 rats ranged from 25 to 400 mg/kg, and doses for groups of 10 mice ranged from 19 to 300 mg/kg; vehicle controls received distilled water. All rats that received 400 mg/kg died by week 2; three males and one female that received 200 mg/kg died during weeks 11-12. Final mean body weights of male rats that received 50, 100, or 200 mg/kg were 96%-85% that of vehicle controls; final mean body weights of female rats receiving the same doses were 95%-89% that of vehicle controls. Sperm count and sperm motility were reduced in male rats that received 100 or 200 mg/kg. Necrosis of the cerebellum, demyelineation in the medulla of the brain, tubular degeneration and/or necrosis of the kidney, lymphoid necrosis of the thymus, and testicular atrophy and/or degeneration occurred in rats that received 400 mg/kg. All mice that received 300 mg/kg died by week 2; deaths of mice that received 150 mg/kg occurred during weeks 4-8 for males and weeks 1-5 for females. Mean body weights of chemically exposed mice surviving to the end of the studies were generally 90%-94% those of vehicle controls. Sperm count and sperm motility were reduced in dosed male mice. Compound-related histopathologic lesions included demyelination of the brain in males and females that received 150 or 300 mg/kg, testicular atrophy in males at all doses, and renal tubular cell degeneration in male mice that received 300 mg/kg. Based on reduced survival, reduced weight gain, and histopathologic lesions in the brain and kidney in rats that received 200 or 400 mg/kg and on reduced survival and histopathologic lesions of the brain in mice that received 150 or 300 mg/kg, doses selected for the 2-year studies of glycidol were 37.5 and 75 mg/kg for rats and 25 and 50 mg/kg for mice. Body Weights and Survival in the Two-Year Studies: Mean body weights of chemically exposed male rats generally ranged from 80% to 94% of those of vehicle controls, and mean body weights of chemically exposed female rats were from 90% to 97% those of vehicle controls. Mean body weights of chemically exposed male mice were similar to those of vehicle controls; mean body weights of chemically exposed female mice were 79%-95% of those of vehicle controls. Virtually all male and female rats that received glycidol died or were killed in a moribund condition as a result of the early induction of neoplastic disease (final survival--male: vehicle control, 16/50; low dose, 0/50; high dose, 0/50; female: 28/50; 4/50; 0/50). Survival of vehicle control male rats was lower than that usually observed; however, specific causes of deaths could not be determined. The survival of male mice and low dose female mice was similar to that of vehicle controls; survival of female mice that resurvival of male mice and low dose female mice was similar to that of vehicle controls; survival of female mice that received 50 mg/kg was lower than that of vehicle controls after week 101 (final survival--male: 33/50; 25/50; 27/50; female: 29/50; 27/50; 17/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Chemical-related nonneoplastic lesions in both rats and mice included hyperkeratosis and epithelial dysplasia of the forestomach. Fibrosis of the spleen was also present in rats of each sex, and cysts of the preputial gland and kidney were present in male mice. Exposure to glycidol induced dose-related increases in the incidences of neoplasms in numerous tissues in both rats and mice (see summary table on page 5 of the Technical Report). In male rats, mesotheliomas arising in the tunica vaginalis and frequently metastasizing to the peritoneum were considered the major cause of early death. Early deaths in female rats were associated with the presence of mammary gland neoplasms. Genetic Toxicology: Glycidol was mutagenic in a variety of in vitro and in vivo short-term tests. Mutagenic activity was observed in S. typhimurium strains TA97, TA98, TA100, TA1535, and TA1537 exposed to glycidol with and without exogenous metabolic activation. Glycidol was positive in the absence of exogenous metabolic activation in the mouse lymphoma assay for induction of trifluorothymidine resistance in L5178Y/TK cells; it was not tested with activation. In cytogenetic tests with CHO cells, glycidol induced both sister chromatid exchanges and chromosomal aberrations in the presence and absence of exogenous metabolic activation. Glycidol induced sex-linked recessive lethal mutations and reciprocal translocations in the germ cells of male D. melanogaster exposed by feeding. The incidence of micronucleated polychromatic erythrocytes was increased in the bone marrow of male B6C3F1 mice administered glycidol by intraperitoneal injection. Conclusions: Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity of glycidol for male F344/N rats, based on increased incidences of mesotheliomas of the tunica vaginalis; fibroadenomas of the mammary gland; gliomas of the brain; and neoplasms of the forestomach, intestine, skin, Zymbal gland, and thyroid gland. There was clear evidence of carcinogenic activity for female F344/N rats, based on increased incidences of fibroadenomas and adenocarcinomas of the mammary gland; gliomas of the brain; neoplasms of the oral mucosa, forestomach, clitoral gland, and thyroid gland; and leukemia. There was clear evidence of carcinogenic activity for male B6C3F1 mice based on increased incidences of neoplasms of the harderian gland, forestomach, skin, liver, and lung. There was clear evidence of carcinogenic activity for female B6C3F1 mice, based on increased incidences of neoplasms of the harderian gland, mammary gland, uterus, subcutaneous tissue, and skin. Other neoplasms that may have been related to the administration of glycidol were fibrosarcomas of the glandular stomach in female rats and carcinomas of the urinary bladder and sarcomas of the epididymis in male mice. Synonym: 2,3-epoxy-1-propanol

Journal Article↗
PubMed1990

NTP Toxicology and Carcinogenesis Studies of Succinic Anhydride (CAS No. 108-30-5) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Succinic anhydride, a food additive, is also used in the manufacture of polymeric materials, pharmaceuticals, and agricultural and industrial chemicals. NTP Toxicology and Carcinogenesis studies were conducted by administering suspensions of succinic anhydride (97% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 or 20 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Chinese hamster ovary (CHO) cells. Twenty-Day or Sixteen-Day and Thirteen-Week Studies: In the 20-day studies in rats, doses of succinic anhydride given on 14 exposure days ranged from 47 to 750 mg/kg. Compound-related deaths occurred in the groups of males that received 375 mg/kg or higher doses and in females that received 187 mg/kg or higher doses. Necrosis and inflammation of the upper respiratory tract were seen in 3/10 male and 3/10 female rats given 750 mg/kg and 2/10 female rats given 375 mg/kg. In the 16-day studies in mice, doses of succinic anhydride given on 12 exposure days ranged from 219 to 3,500 mg/kg. All animals that received 875 mg/kg or higher doses of succinic anhydride died before the end of the studies. No compound-related lesions were seen in male or female mice examined from the 438 mg/kg dose group. In the 13-week studies in rats, doses of succinic anhydride ranged from 25 to 400 mg/kg for males and from 12.5 to 200 mg/kg for females. Deaths of 8/10 male rats that received 400 mg/kg and 4/10 males and 5/10 females that received 200 mg/kg were compound related. At necropsy, the mean body weights of male rats that received 200 or 400 mg/kg were 9% or 15% lower than that of vehicle controls, whereas the mean body weights of dosed and vehicle control female rats were similar. No compound-related gross or microscopic lesions were observed. In the 13-week studies in mice, doses of succinic anhydride ranged from 37 to 600 mg/kg. All 10 males and 8/10 females that received 600 mg/kg and 2/10 males and 2/10 females that received 300 mg/kg died before the end of the studies. The final mean body weights of mice that received 150 or 300 mg/kg were 13% or 9% lower than that of vehicle controls for males and 8% or 7% lower for females. Mild inflammation of the stomach was observed in 7/10 male mice that received 150 mg/kg and 5/10 males that received 300 mg/kg compared with 2/10 vehicle controls. Based primarily on the effects of administration of succinic anhydride on survival and mean body weights of rats and mice, doses for the 2-year studies were 0, 50, or 100 mg/kgto groups of 60 rats of each sex; 0, 38, or 75 mg/kg to groups of 50 male mice; and 0, 75, or 150 mg/kg to groups of 50 female mice. Succinic anhydride was administered as a suspension in corn oil by gavage, 5 days per week for 103 weeks. Body Weights and Survival in the Two-Year Studies: Mean body weights of high dose rats were 5%-11% lower than those of vehicle controls during the second year of the studies. No significant differences in survival after 2 years were observed between any groups of rats of either sex (male: vehicle control, 36/60; low dose, 33/60; high dose, 32/60; female: 31/60; 27/60; 27/60). For mice, mean body weights of high dose males were generally 5%-12% lower than those of vehicle controls throughout the study. Mean body weights of high dose female mice were 10%-32% lower than those of vehicle controls; mean body weights of low dose female mice were 10%-20% lower than those of vehicle controls. The survival of high dose male mice was significantly greater than that of vehicle controls after week 77 (survival after 2 years--male: 27/50; 30/50; 42/50; female: 37/50; 38/50; 41/50). No other differences in survival were observed between any groups of mice of either sex. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: At no site in rats or mice was there a chemical-related increase in the incidence of nonneoplastic or neoplastic lesions. A sufficient number of animals in each dose group lived long enough to allow evaluation of the potential carcinogenicity ofr of animals in each dose group lived long enough to allow evaluation of the potential carcinogenicity of succinic anhydride. Genetic Toxicology: Succinic anhydride was not mutagenic in S. typhimurium with or without exogenous metabolic activation. The chemical did not induce sister chromatid exchanges or chromosomal aberrations in cultured CHO cells in the presence or absence of exogenous metabolic activation. Conclusions: Under the conditions of these 2-year studies, there was no evidence of carcinogenic activity of succinic anhydride for male or female F344/N rats given 50 or 100 mg/kg succinic anhydride. There was no evidence of carcinogenic activity for male B6C3F1 mice given 38 or 75 mg/kg succinic anhydride or for female B6C3F1 mice given 75 or 150 mg/kg. Synonyms: butanedioic anhydride; dihydro-2,5-furandione; 2,5-diketotetrahydrofuran; succinic acid anhydride; succinyl anhydride; succinyl oxide; tetrahydro-2,5-dioxofuran

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