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PubMed2002

[Post-traumatic anosmia: description of a clinical case, proposal of a standardized protocol and medico-legal comments].

Man's olfactory perception is considerably limited compared to that of other animals; this sense is, however, extremely important in our social lives: it helps us to "savour" our food, it enables us to appreciate perfumes and, even more important, to pick up smells that signal a danger, such as a gas leak or a fire. We describe the clinical case of a patient with anosmia and hypogeusia that appeared immediately after suffering a concussive head injury. We go through the diagnostic protocol for medico-legal assessment of hypoanosmias previously described in the literature, which includes a clinical and an imaging section. In 9% of all anosmic patients, a traumatic event precedes the onset of the disorder, with repercussions on the olfactory channels and centres of the peripherical and/or central nervous system. The overall rate of anosmia following head injury is estimated to be around 7.5%. Among the principal causes of anosmia, those of medico-legal interest constitute 35% of the total. On the basis of our personal experience and of clinical studies conducted by other Authors, we propose that a bioptic investigation of the olfactory mucosa be added to the existing protocol. The olfactory neuroepithelium of patients suffering from post-traumatic anosmia, in fact, evidences some characteristic degenerative aspects. In conclusion, we report several comments regarding the quantification of the reduction of the olfactory function in different areas of medico-legal interest.

Adult↗
PubMed2000

NTP Toxicology and Carcinogenesis Studies of Methyleugenol (CAS NO. 93-15-2) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Methyleugenol is used as a flavoring agent in jellies, baked goods, nonalcoholic beverages, chewing gum, candy, pudding, relish, and ice cream. It is also used as a fragrance in perfumes, creams, lotions, detergents, and soaps. Methyleugenol has also been used as an insect attractant in eradication programs and as an anesthetic in rodents. Methyleugenol was nominated for testing because of its widespread use and because of its structural resemblance to safrole, a known carcinogen, and isosafrole and estragole. Male and female F344/N rats and B6C3F1 mice received methyleugenol (approximately 99% pure) in 0.5% methylcellulose by gavage for 14 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse peripheral blood erythrocytes. 14-WEEK STUDY IN RATS: Groups of 9 or 10 male and 10 female F344/N rats were administered 0, 10, 30, 100, 300, or 1,000 mg methyleugenol/kg body weight in 0.5% methylcellulose by gavage 5 days per week for 14 weeks. A water control group of 10 male and 10 female rats received deionized water by gavage. All rats survived until the end of the study. The final mean body weights of 300 and 1,000 mg/kg males and of all dosed groups of females were significantly less than those of the vehicle controls. Erythrocyte microcytosis was demonstrated by decreased mean cell volumes in 300 mg/kg males and 1,000 mg/kg males and females. There was evidence of a thrombocytosis at all time points, demonstrated by increased platelet counts in the 100 mg/kg or greater groups. The serum activities of alanine aminotransferase and sorbitol dehydrogenase were increased in the 100 mg/kg or greater rats at various time points, suggesting hepatocellular injury. Additionally, bile acid concentrations were generally increased in the 300 and 1,000 mg/kg groups at all time points, consistent with cholestasis or altered hepatic function. A hypoproteinemia and hypoalbuminemia, evidenced by decreased total protein and albumin concentrations, occurred in rats in the 300 and 1,000 mg/kg groups at all time points. Liver weights of 100, 300, and 1,000 mg/kg males and 300 and 1,000 mg/kg females and testis weights of 1,000 mg/kg males were significantly increased. Increased incidences of liver lesions occurred in 300 and 1,000 mg/kg males and females and hepatocellular adenoma occurred in one 1,000 mg/kg male. The incidences of atrophy and chronic inflammation of the mucosa of the glandular stomach were significantly increased in rats administered 300 or 1,000 mg/kg. Increased incidences of adrenal gland cortical hypertrophy and/or cytoplasmic alteration in the submandibular gland occurred in the 100 mg/kg or greater groups. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice received methyleugenol in 0.5% methylcellulose by gavage at doses of 0, 10, 30, 100, 300, or 1,000 mg/kg, 5 days per week for 14 weeks. A water control group of 10 male and 10 female mice received deionized water by gavage. All but one male and all females receiving 1,000 mg/kg died before the end of the study. The mean body weight gains of mice in the 300 mg/kg groups were significantly less than those of the vehicle controls. The only clinical finding was toxicity manifested as generalized morbidity in mice administered 1,000 mg/kg. Liver weights of 30, 100, and 300 mg/kg males and of 300 mg/kg females were significantly increased. Male mice administered 10 or 30 mg/kg had significantly lower cauda epididymis, epididymis, and testis weights; males receiving 100 mg/kg had significantly lower spermatozoal concentrations. Increased incidences of liver lesions occurred in 1,000 mg/kg males and 300 and 1,000 mg/kg females. The incidences of lesions of the glandular stomach were increased in one or more groups administered 30 mg/kg or greater. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats received methyleugenol in 0.5% methylcellulose by gavage at doses of 37, 75, or 150 mg/kg, 5 days per week for 105 weeks; groups of 60 male and 60 female rats received the 0.5% me60 female rats received the 0.5% methylcellulose vehicle only. Stop-exposure groups of 60 male and 60 female rats received 300 mg/kg in 0.5% methylcellulose by gavage for 52 weeks followed by just the 0.5% methylcellulose vehicle for the remaining 53 weeks of the study. Special study groups of 10 male and 10 female rats administered 36, 75, 150, or 300 mg/kg were designated for toxicokinetic studies. Survival and Body Weights: All 150 and 300 mg/kg males died before the end of the study, and survival of 150 mg/kg females was slightly less than that of the vehicle controls. Mean body weights of all dosed groups of rats were less than those of the vehicle controls throughout most of the 2-year study. Pathology Findings: Chemical-related liver neoplasms occurred in all dosed groups of rats and included hepatocellular adenoma, hepatocellular carcinoma, hepatocholangioma, and hepatocholangiocarcinoma; at 2 years, there were positive trends in the incidences of hepatocellular adenoma, carcinoma, and adenoma or carcinoma (combined) in core study rats and in the numbers of rats with multiple liver neoplasms. Nonneoplastic lesions included eosinophilic and mixed cell foci, hepatocellular hypertrophy, oval cell hyperplasia, cystic degeneration, and bile duct hyperplasia (females); the incidences of these lesions in dosed groups of male and female rats were increased at 6 months, 12 months, and/or 2 years. Chemical-related neoplasms and nonneoplastic lesions of the glandular stomach included benign and malignant neuroendocrine tumors in the 150 and 300 mg/kg groups and females in the 75 mg/kg group. In all dosed groups of rats at all time points, the incidences of mucosal atrophy were significantly greater than in the vehicle controls. Neuroendocrine cell hyperplasia was observed in females at 6 months and males and females at 12 months and at 2 years. In core study female rats, there was a positive trend in the incidences of squamous cell papilloma or carcinoma (combined) of the forestomach, and the incidence in the 150 mg/kg group exceeded the historical control range. The incidences of renal tubule proliferative lesions in male rats were suggestive of a neoplastic effect in the kidney. Therefore, additional step sections of the kidneys of male rats were prepared. The incidences of renal tubule hyperplasia and adenoma in the extended evaluation and the combined incidences of standard and step sections in the 75, 150, and 300 mg/kg groups were greater than those in the vehicle controls. The incidences of nephropathy were increased in all dosed groups of females, and the increase was significant in the 300 mg/kg group. In dosed groups of male rats, there was a positive trend in the incidences of malignant mesothelioma, and the incidences were significantly greater in 150 and 300 mg/kg males than in the vehicle controls. The incidences of mammary gland fibroadenoma in 75 and 150 mg/kg males were significantly increased. The incidences of fibroma of the subcutaneous tissue in 37 and 75 mg/kg males and the combined incidences of fibroma or fibrosarcoma in 37, 75, and 150 mg/kg males were significantly increased. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice received methyleugenol in 0.5% methylcellulose by gavage at doses of 0, 37, 75, or 150 mg/kg for 105 weeks. Special study groups of 10 male and 10 female mice administered 37, 75, or 150 mg/kg were designated for toxicokinetic studies. Survival and Body Weights: Survival of all dosed groups of male mice was similar to that of the vehicle controls. Survival of dosed groups of females was significantly less. Mean body weights of dosed mice were generally less than those of the vehicle controls throughout the studies. Pathology Findings: Chemical-related increases in the incidences of liver neoplasms and nonneoplastic lesions in mice included hepatocellular adenoma and carcinoma, hepatoblastoma, hepatocholangiocarcinoma, eosinophilic foci, oval cell hyperplasia, bile duct hyperplasia, hemosiderin pigmentation, chronic active inflammation, and hematopoietic cell proliferation. In all dosed groups ofmales and females, the incidences of hepatocellular neoplasms and the multiplicity of neoplasms were generally greater than in the vehicle controls. The incidences of hepatoblastoma were significantly increased in all dosed groups of females and slightly increased in 150 mg/kg males. Hepatocholangiocarcinoma was observed in 150 mg/kg females. The incidences of eosinophilic foci, oval cell hyperplasia, portal hypertrophy, hepatocyte necrosis, hematopoietic cell proliferation, bile duct hyperplasia, and hemosiderin pigmentation were significantly increased in two or more dosed groups of male and/or female mice. The incidences of glandular ectasia, mucosal atrophy, chronic active inflammation, epithelial hyperplasia, and neuroendocrine cell hyperplasia of the glandular stomach were increased in one or more dosed groups of male and female mice. In addition, malignant neuroendocrine tumors were observed in the glandular stomach of two 150 mg/kg male mice; one male in this group had a carcinoma. TOXICOKINETIC STUDIES: Methyleugenol is rapidly absorbed following oral administration to rats and mice. The kinetic data are consistent with rapid clearance from the blood, metabolism in the liver, and excretion of the parent and various metabolites in the urine. GENETIC TOXICOLOGY: Methyleugenol was not mutagenic in S. typhimurium strain TA98, TA100, TA1535, or TA1537, with or without exogenous metabolic activation (S9). In cytogenetic tests with cultured Chinese hamster ovary cells, methyleugenol induced sister chromatid exchanges in the presence of S9, but no induction of chromosomal aberrations was noted in cultured Chinese hamster ovary cells following exposure to methyleugenol, with or without S9. In vivo, no increase in the frequency of micronucleated normochromatic erythrocytes was seen in male or female mice administered methyleugenol by gavage for 14 weeks. PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL: A physiologically based pharmacokinetic (PBPK) model resulting from intravenous and oral exposure was created to characterize tissue concentrations of methyleugenol in rats and mice. Data used to create the model were obtained from the literature or from current studies. The primary conclusions that can be reached from the PBPK model are: 1) absorption of oral doses of methyleugenol in rats and mice is rapid and complete, 2) distribution of methyleugenol to tissues is not hampered by capillary permeability, and 3) metabolism of methyleugenol is saturable and must have some extrahepatic component in the mouse. Model-based plasma methyleugenol concentrations were not found to be good dosimeters for evaluating neoplasm dose-response data. CONCLUSIONS: Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity of methyleugenol in male and female F344/N rats based on the increased incidences of liver neoplasms and neuroendocrine tumors of the glandular stomach in male and female rats and the increased incidences of kidney neoplasms, malignant mesothelioma, mammary gland fibroadenoma, and subcutaneous fibroma and fibroma or fibrosarcoma (combined) in male rats. A marginal increase in the incidence of squamous cell neoplasms of the forestomach may have been related to methyleugenol administration in female rats. There was clear evidence of carcinogenic activity of methyleugenol in male and female B6C3F1 mice based on the increased incidences of liver neoplasms. Neuroendocrine tumors of the glandular stomach in male mice were also considered related to methyleugenol administration. In male and female rats and mice, methyleugenol administration caused significant increases in nonneoplastic lesions of the liver and glandular stomach. Synonyms: 1-Allyl-1,2-dimethoxybenzene; 4-allylveratrole; 4-allyl-1,2-dimethoxy-benzene; 1,2-dimethoxy-4-allylbenzene; 3,4-dimethoxyallylbenzene; ENT 21040; 1-(3,4-dimethoxyphenyl)-2-propene; eugenol methyl ether; 1,3,4-eugenol methyl ether; veratrole methyl ether.

Journal Article↗
PubMed2001

[Study on the essential oil components in Thymus quinquecostatus Celak].

AIM: To analyse the essential oil components of Thymus quinquecostatus Celak. METHODS: Gas chromatography/mass spectrometry were used. RESULTS: A total of 78 components were separated. 34 of them were identified, which accounted for 95.93% of the total peak area. The main constituents are o-cymene, carvacrol, caryophyllene, 2-isopropyl-1-methoxy-4-methylbenzene and gamma-terpene. CONCLUSION: Thymus quinquecostatus Celak has perfume and medical development value.

Cymenes↗
PubMed1999

Aromatic drugs in Unani medicine with special reference to Kitabul-Mia-Lil-Masihi.

This is an established fact since time immemorial that, the aroma plays a vital role in the human beings and even in animals. The aromatic plants and aromatic chemicals contained in them has also significance in our day to day living. Process of distillation as adopted and described by Unani physicians confirms the claim that, they were aware of the importance of aromatic drugs and perfumes. There is a vast literature scattered in existing Unani medical books, which shows their intelligential towards the knowledge of herbal drugs including aromatic plants. 'Kitabul-Mia-Lil-Masihi is a book on Unani medicine. Its 17th Chapter consists of aromatic drugs exclusively. The drugs have been classified and presented here under different headings.

Aromatherapy↗
PubMed1997

NTP Toxicology and Carcinogenesis Studies of t-Butylhydroquinone (CAS No. 1948-33-0) in F344/N Rats and B6C3F(1) Mice (Feed Studies).

t -Butylhydroquinone is used as an antioxidant in cosmetic products such as lipsticks, eye shadows, perfumes, blushers, and skin care preparations at concentrations ranging from 0.1% to 1.0%; the chemical is also used at concentrations up to 0.02% in oils, fats, and meat products to prevent rancidity, and as a polymerization inhibitor for various polyunsaturated polyesters (CIR, 1986). t-Butylhydroquinone was nominated for toxicity and carcinogenicity testing by the Food and Drug Administration. Toxicology and carcinogenicity studies were conducted in F344/N rats and B6C3F(1) mice. Mice were exposed to t-butyl hydroquinone (99% pure) in feed for 13 weeks or 2 years. For rats, exposure to t-butylhydroquinone began in utero and continued through lactation. After weaning, pups were fed diets containing the same levels of t-butylhydroquinone as those given to their respective dams for 13 weeks or for up to 30 months. The oral route of administration was selected for these studies because t-butylhydroquinone is used as a food additive and human exposure occurs predominantly through this route. In addition to the oral route of exposure, rats were exposed prenatally because perinatal exposure to butylated hydroxytoluene (a structurally related chemical) induced hepatocellular neoplasms in rats. Genetic toxicology studies were conducted in Salmonella typhimurium and cultured Chinese hamster ovary cells in vitro and in mouse bone marrow cells in vivo. 13-WEEK STUDY IN RATS: In the perinatal exposure phase of the 13-week study, groups of 10 female rats (F(0)) were fed 0, 2,500, 5,000, 10,000, 20,000, or 40,000 ppm t-butylhydroquinone from 2 weeks prior to cohabitation until the F(1) pups were weaned. F(0) females exposed to 20,000 or 40,000 ppm did not litter. The number of pup deaths in the 5,000 and 10,000 ppm groups was greater than that in the control group, and the average number of surviving pups per litter in the 10,000 ppm group was less than that in the control group. Mean body weights of pups exposed perinatally to 5,000 or 10,000 ppm were lower than that of the controls at the time of weaning. Groups of 10 male and 10 female F(1) rats continued to receive diets containing 0, 2,500, 5,000, or 10,000 ppm t-butylhydroquinone for 13 weeks fol lowing weaning. These dietary levels corresponded to approximately 200, 400, or 800 mg t-butylhydro quinone/kg body weight (males) or 200, 400, or 750 mg/kg (females) per day. All rats survived to the end of the study. The final mean body weights of males and females in the 5,000 and 10,000 ppm groups were significantly lower than those of the controls, as was the mean body weight gain of males exposed to 10,000 ppm. However, interpretation of these findings was complicated by the significantly lower initial mean body weights of the 10,000 ppm groups. Differences in initial body weights were due to in utero exposure to t-butylhydroquinone. Feed consumption by exposed groups of rats was lower than that by controls at week 2, and feed consumption by 5,000 and 10,000 ppm males and 10,000 ppm females was slightly lower than that by controls at the end of the study. Hair discoloration in all exposed groups of rats, except females exposed to 2,500 ppm, was the only clinical observation considered related to chemical exposure. The mean spermatid count, spermatid heads per testis, and spermatid heads per gram of testis were significantly decreased in males exposed to 5,000 ppm. The estrous cycles of females exposed to 2,500 or 5,000 ppm were significantly longer than that of the controls. There were no biologically significant changes in clinical pathology parameters or in organ weights. Increased incidences of hyperplasia of the nasal respiratory epithelium were observed in males exposed to 5,000 ppm and males and females exposed to 10,000 ppm, and an increased incidence of nasal exudate was observed in males in the 10,000 ppm group. Increased incidences of pigmentation were observed in the spleen of male and female rats exposed to 5,000 or 10,000 ppm. Based on lower final mean body weights wer final mean body weights and decreased feed consumption in males and females exposed to 10,000 ppm t-butylhydroquinone, exposure concentrations selected for the long-term rat study were 1,250, 2,500, and 5,000 ppm. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were fed diets containing 0, 2,500, 5,000, 10,000, 20,000, or 40,000 ppm t-butylhydroquinone for 13 weeks. These dietary levels corresponded to approximately 440, 880, 1,950, 4,000, and 8,400 mg t-butylhydro quinone/kg body weight (males) or 500, 1,100, 2,200, 4,600, and 9,000 mg/kg body weight (females) per day. There were no exposure-related deaths. Final mean body weights and body weight gains of males and females exposed to 10,000, 20,000, or 40,000 ppm were significantly less than those of the controls. Feed consumption by exposed mice appeared to be similar to that by controls, but there was excessive scatter of feed by mice exposed to 10,000, 20,000, or 40,000 ppm. Therefore, feed consumption by male and female mice in these groups was likely less than that by controls. Significant increases in segmented neutrophil counts occurred at week 3 and at the end of the study in females exposed to 10,000 ppm and males and females exposed to 20,000 or 40,000 ppm. Left caudal, left epididymis, and left testis weights of males exposed to 10,000 or 40,000 ppm were generally significantly lower than those of the controls. The estrous cycle of females exposed to 40,000 ppm was significantly longer than that of the control group. There were no biologically significant differences in organ weights. Increased incidences and severities of mucosal hyperplasia were observed in the forestomach of males exposed to 20,000 or 40,000 ppm and in females exposed to 10,000, 20,000, or 40,000 ppm, and increased incidences of inflammation were observed in the nose and skin of males and females exposed to 10,000, 20,000, or 40,000 ppm. Increased incidences of hyperplasia also occurred in the skin of males and females exposed to 10,000, 20,000, or 40,000 ppm. Based on lower final mean body weights, increased incidences of inflammation of the nose and skin, increased incidences of forestomach mucosal hyperplasia, and increased severity of nonneoplastic lesions observed in mice exposed to 10,000, 20,000, or 40,000 ppm, exposure concentrations selected for the 2-year study were 1,250, 2,500, and 5,000 ppm. LONG-TERM STUDY IN RATS: In the perinatal exposure phase of the long-term study, groups of 60 female F(0) rats were fed diets containing 0, 1,250, 2,500, or 5,000 ppm t-butyl hydroquinone, beginning 2 weeks prior to cohabitation and continuing until F(1) pups were weaned. Following weaning, groups of 70 male and 70 female F(1) rats continued to receive diets containing 0, 1,250, or 5,000 ppm, and groups of 68 male and 68 female rats continued to receive diets containing 2,500 ppm. The duration of dosing in feed was 123 weeks post-weaning for males and 129 weeks for females. These exposure concentrations resulted in daily doses of approximately 50, 100, and 200 mg t-butylhydro quinone/kg body weight (males) or 60, 120, and 240 mg/kg (females). Ten male and ten female F(1) rats from each exposure group were evaluated at 3 months. Survival, Body Weights, Feed Consumption, and Clinical Findings: Survival of females exposed to 5,000 ppm was significantly greater than that of the control group. The mean body weights of males and females exposed to 5,000 ppm were generally less than those of the controls throughout the study. Feed consumption by exposed groups was similar to that by controls. Clinical findings of hair discoloration in exposed groups of males and females were considered to be related to chemical exposure. Pathology Findings: No increased neoplasm incidences in male or female rats were attributed to t-butylhydroquinone exposure. The incidences of mammary gland fibroadenoma and fibroadenoma or adenoma (combined) were significantly decreased in males exposed to 1,250 ppm and in all exposed groups of females; and combined incidences of mammary gland fibroadenoma, adenoma, or carcinoma were significantly decreased in all groups of exposed females. The decreases occurred with significant negative trends. Incidences of renal cysts and inflammation were generally increased in exposed groups of male rats. 2-YEAR STUDY IN MICE: Groups of 60 male and 60 female mice received 0, 1,250, 2,500, or 5,000 ppm t-butylhydroquinone in feed for 104 to 105 weeks. These exposure concentrations resulted in daily doses of approximately 150, 300, or 600 mg t-butylhydroquinone/kg body weight (males) or 150, 300, or 700 mg/kg (females). As many as 10 males and 10 females from each exposure group were evaluated at 15 months. Survival, Body Weights and Feed Consumption: Survival of all exposed groups of males and females was similar to that of the control groups. Mean body weights of the 5,000 ppm groups were generally lower than those of the control groups from week 13 until the end of the study. Feed consumption by exposed groups of males and females was similar to that by the controls. There were no biologically significant differences in clinical pathology parameters between control and exposed groups of mice. Pathology Findings: No increased incidences of neoplasms or nonneoplastic lesions in male or female mice were considered to be related to t-butylhydroquinone exposure. GENETIC TOXICOLOGY: t-Butylhydroquinone was not mutagenic in any of four strains of Salmonella typhimurium, with or without liver S9 metabolic activation enzymes. It did, however, induce sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells in the presence, but not the absence, of S9. No increase in the frequency of micronucleated erythrocytes was observed in bone marrow of male mice treated with t-butylhydroquinone. CONCLUSIONS: Under the conditions of this long-term feed study, there was no evidence of carcinogenic activity of t-butylhydroquinone in male or female F344/N rats exposed to 1,250, 2,500, or 5,000 ppm. Under the conditions of this 2-year feed study, there was no evidence of carcinogenic activity of t-butylhydroquinone in male or female B6C3F(1) mice exposed to 1,250, 2,500, or 5,000 ppm. Exposure of rats to t-butylhydroquinone in feed resulted in decreased incidences of mammary gland neoplasms in males and females. Synonyms: Tert-butyl-hydroquinone; 2-(1,1-dimethylethyl)-1,4-benzenediol; 2-tert-butylhydroquinone; mono-tert-butylhydroquinone; tert-butyl-1,4-benzenediol: mono-tertiarybutylhydroquinone; 2-tert-butyl-1,4-benzenediol; 2-(1,1-dimethyl)hydroquinone; 2-(tert-butyl)-p-hydroquinone; TBHQ; MTBHQ Trade Names: Sustane; Tenox TBHQ; Banox 20BA

Journal Article↗
PubMed1995

NTP Toxicology and Carcinogenesis Studies of t -Butyl Alcohol (CAS No. 75-65-0) in F344/N Rats and B6C3F1 Mice (Drinking Water Studies).

t -Butyl alcohol is widely used in the manufacture of perfumes and a variety of cosmetics. It is also used as a raw material in the production of isobutylene, which may be used to produce methyl tertiary butyl ether, a common gasoline additive, or to produce butyl elastomers used in the production of automobile tires. Male and female F344/N rats and B6C3F1 mice were given t -butyl alcohol (greater than 99% pure) in drinking water for 13 weeks or 2 years. The genetic toxicity of t -butyl alcohol was assessed by testing the ability of the chemical to induce mutations in various strains of Salmonella typhimurium and in L5178Y mouse lymphoma cells, sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells, and by measuring the frequency of micronucleated erythrocytes in mouse peripheral blood. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were given 0, 2.5, 5, 10, 20, or 40 mg/mL t -butyl alcohol in drinking water for 13 weeks. All males and six females given 40 mg/mL died during the study. Final mean body weights of 10 and 20 mg/mL males and of 40 mg/mL females were 12%, 17%, or 21% less than those of the corresponding controls, respectively. Serum sorbitol dehydrogenase activities in 10 and 20 mg/mL males were greater than that in the controls after 13 weeks. Serum alanine aminotransferase activity in 40 mg/mL females was greater than that in the controls after 2 weeks and greater in all exposed females after 13 weeks. Urine volumes of 10, 20, and 40 mg/mL males and females decreased, and urine specific gravity values increased. Transitional epithelial hyperplasia and inflammation of the urinary bladder were observed in 20 and 40 mg/mL males and 40 mg/mL females. Absolute and relative liver weights of all exposed groups of females and relative liver weights of 5, 10, and 20 mg/mL males were significantly greater than those of the controls. Absolute and relative kidney weights of all exposed groups of males and females were significantly greater than those of the controls. Incidences of mineralization of the kidney were significantly increased in 10, 20, and 40 mg/mL males. The severity of nephropathy in 2.5, 5, 10, and 20 mg/mL males was significantly greater than that of the controls as was the accumulation of hyaline droplets in the kidney of 5, 10, and 20 mg/mL males. The incidences of nephropathy in 10, 20, and 40 mg/mL females were significantly greater than that of the controls. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were given 0, 2.5, 5, 10, 20, or 40 mg/mL t -butyl alcohol in drinking water for 13 weeks. The deaths of two males and one female in the 40 mg/mL group were attributed to exposure to t -butyl alcohol. The final mean body weights of 20 and 40 mg/mL males and 40 mg/mL females were significantly lower than those of the controls. There were no biologically significant differences in hematology parameters of exposed and control groups of mice. Transitional epithelial hyperplasia and inflammation were observed in the urinary bladder of 20 and 40 mg/mL males and 40 mg/mL females. 2-YEAR STUDY IN RATS: Groups of 60 F344/N rats were given 0, 1.25, 2.5, or 5 mg/mL t -butyl alcohol (males) or 0, 2.5, 5, or 10 mg/mL t -butyl alcohol (females) in drinking water for 2 years. These correspond to average daily doses of approximately 90, 200, or 420 mg t -butyl alcohol/kg body weight for males and approximately 180, 330, or 650 mg t -butyl alcohol/kg body weight for females. Ten rats per group were evaluated after 15 months of chemical administration. Survival, Body Weights, and Water Consumption: Survival rates of 5 mg/mL males and 10 mg/mL females were significantly lower than those of the controls. The final mean body weights of exposed groups of males were 15% to 24% lower than that of the controls, and the final mean body weight of 10 mg/mL females was 21% lower than that of the controls. Water consumption by males increased with dose; water consumption by females decreased with dose. Hematology and Urinalysis: At the 15-month inte. Hematology and Urinalysis: At the 15-month interim evaluation, there were no significant differences in hematology parameters in males and females, and there were no significant differences in urinalysis parameters in males. Females given 5 or 10 mg/mL had increased urine specific gravities and decreased urine volumes. Pathology Findings: At the 15-month interim evaluation, relative kidney weights of 2.5 and 5 mg/mL males and absolute and relative kidney weights of 2.5, 5, and 10 mg/mL females were significantly greater than those of the controls. At 2 years, the incidence of mineralization in the kidney increased with dose and that of 5 mg/mL males was significantly greater than that of the controls. In the standard evaluation at the end of the study, the incidences of focal renal tubule hyperplasia and of adenoma were increased in exposed males and a carcinoma was observed in one 5 mg/mL male. Renal tubule hyperplasia occurred in one 10 mg/mL female. An extended evaluation of the kidney identified additional male rats with hyperplasia (control, 11/50; 1.25 mg/mL, 13/50; 2.5 mg/mL, 11/50; 5 mg/mL, 19/50) and renal tubule adenoma (7/50, 8/50, 15/50, 10/50); renal tubule carcinomas were identified in two 1.25 mg/mL males and in one 2.5 mg/mL male. Renal tubule adenoma was identified in one 5 mg/mL male from the 15-month extended evaluation. In the standard and extended evaluations combined, there were dose-related increased incidences of hyperplasia and adenoma. The severity of nephropathy and the incidence and severity of transitional cell hyperplasia of the kidney were increased in exposed male and female rats. Linear foci of mineralization were present in the renal papilla of exposed males. 2-YEAR STUDY IN MICE: Groups of 60 male and 60 female B6C3F1 mice were given 0, 5, 10, or 20 mg/mL t -butyl alcohol in drinking water for 2 years. Exposure levels of 5, 10, or 20 mg/mL delivered average daily doses of approximately 540, 1,040, or 2,070 mg t -butyl alcohol/kg body weight to males and approximately 510, 1,020, or 2,110 mg/kg to females. Survival, Body Weights, and Water Consumption: Survival of 20 mg/mL males was significantly lower than that of the controls. The final mean body weights of exposed groups of males were similar to those of the controls. The mean body weights of females given 20 mg/mL were 10% to 15% lower than those of the controls from week 13 to the end of the study. Water consumption by exposed groups of males and females was similar to that by the controls. Pathology Findings: Incidences of thyroid gland follicular cell hyperplasia were significantly increased in all exposed groups of males and in 10 and 20 mg/mL females. The incidence of follicular cell adenoma or carcinoma (combined) was marginally increased in 10 mg/mL males (0 mg/mL, 1/60; 5 mg/mL, 0/59; 10 mg/mL, 4/59; 20 mg/mL, 2/57). The incidence of follicular cell adenoma was significantly increased in 20 mg/mL females (2/58, 3/60, 2/59, 9/59). The incidences of chronic inflammation and transitional epithelial hyperplasia of the urinary bladder were increased in 20 mg/mL males and to a lesser extent in 20 mg/mL females. GENETIC TOXICOLOGY: t -Butyl alcohol was tested for induction of genetic damage in vitro and in vivo, and all results were negative. In vitro, t -butyl alcohol was negative in Salmonella typhimurium and mouse lymphoma cell mutation tests, and it did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells. These in vitro studies were conducted with and without metabolic activation (S9). In vivo, no increase in micronucleated erythrocytes was observed in peripheral blood samples from mice administered t -butyl alcohol in drinking water for 13 weeks. CONCLUSIONS: Under the conditions of these 2-year drinking water studies, there was some evidence of carcinogenic activity of t -butyl alcohol in male F344/N rats based on increased incidences of renal tubule adenoma or carcinoma (combined). There was no evidence of carcinogenic activity in female F344/N rats receiving 2.5, 5, or 10 mg/mL t -butyl alcohol. There was equivocal evidence of carcinogenic activity of t -butyl alcohol in male B6C3F1 mice based on the marginally increased incidences of follicular cell adenoma or carcinoma (combined) of the thyroid gland. There was some evidence of carcinogenic activity of t -butyl alcohol in female B6C3F1 mice based on increased incidences of follicular cell adenoma of the thyroid gland. Exposure to t -butyl alcohol was associated with mineralization and renal tubule hyperplasia in male rats, transitional epithelial hyperplasia and increased severity of nephropathy of the kidney in male and female rats, follicular cell hyperplasia of the thyroid gland in male and female mice, and chronic inflammation and hyperplasia of the urinary bladder in male mice and to a lesser extent in female mice. Synonyms: 2-Methyl-2-propanol, 2-methylpropan-2-ol, TBA, t -butanol, tertiary butyl alcohol, t -butyl hydroxide, trimethyl carbinol, trimethyl methanol

Journal Article↗
PubMed1993

NTP Toxicology and Carcinogenesis Studies of 3,4-Dihydrocoumarin (CAS No. 119-84-6) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

3,4-Dihydrocoumarin was nominated by the Food and Drug Administration and the National Cancer Institute for study because of its widespread use as a flavoring agent in beverages, gelatins, puddings, candy, and other food items; as a fragrance in perfumes, creams, and cosmetics; and because of interest in the structure-activity relationships of the coumarin derivatives. Toxicity and carcinogenicity studies were conducted by administering 3,4-dihydrocoumarin (99% pure) in corn oil by gavage to groups of male and female F344/N rats and B6C3F1 mice for 16 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and peripheral blood cells of mice. 16-DAY STUDY IN RATS: Groups of five male and five female rats received 3,4-dihydrocoumarin in corn oil by gavage at doses of 0, 190, 375, 750, 1,500, or 3,000 mg/kg body weight 5 days per week for a total of 12 doses in a 16-day period. All male and female rats given 3,000 mg/kg, and four male rats and five female rats given 1,500 mg/kg died. Body weight gains and final mean body weights of rats receiving 190, 375, or 750 mg/kg were similar to those of the controls. There were no clinical findings of organ-specific toxicity or evidence of impaired blood coagulation. 16-DAY STUDY IN MICE: Groups of five male and five female mice received 3,4-dihydrocoumarin in corn oil by gavage at doses of 0, 140, 280, 560, 1,125, or 2,250 mg/kg body weight 5 days per week for a total of 12 doses in a 16-day period. All mice given 2,250 mg/kg died. Body weight gains and final mean body weights of mice receiving 140, 280, 560, and 1,125 mg/kg were similar to those of the controls. There were no clinical findings of organ-specific toxicity or evidence of impaired blood coagulation. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats received 3,4-dihydrocoumarin in corn oil by gavage at doses of 0, 75, 150, 300, 600, or 1,200 mg/kg body weight 5 days per week for 13 weeks. Two male rats and five female rats given 1,200 mg/kg died. The body weight gain and final mean body weight of male rats that received 1,200 mg/kg were significantly lower than those of the controls, but the final mean body weights of other dosed groups of male rats and all dosed groups of female rats were similar to or slightly greater than those of the controls. Platelet counts were significantly lower in males and females receiving 600 and 1,200 mg/kg and in females receiving 300 mg/kg. Hemoglobin and hematocrit values and erythrocyte counts were significantly lower in males that received 300 mg/kg or more. The absolute and relative liver and kidney weights of males and females receiving 600 and 1,200 mg/kg were significantly greater than those of the controls. Hepatocellular hypertrophy was observed in rats given 300, 600, and 1,200 mg/kg. The high dose selected for the 2-year study was 600 mg/kg, which was below the level at which mortality, lower final mean body weights, and treatment-related liver lesions were observed. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice received 3,4-dihydrocoumarin in corn oil by gavage at doses of 0, 100, 200, 400, 800, or 1,600 mg/kg body weight 5 days per week for 13 weeks. Eight male and five female mice receiving 1,600 mg/kg died. Deaths in other groups were attributed to dosing accidents. Final mean body weights of dosed male and female mice were similar to those of the controls, and there were no treatment-related changes in any hematologic parameters. The absolute and relative liver weights of males and females that received 1,600 mg/kg and the relative kidney weight of males that received 1,600 mg/kg were significantly greater than those of the controls. No treatment-related lesions were noted. The high dose selected for the 2-year study was 600 mg/kg, which was below the level at which mortality, lower final mean body weights, and treatment-related liver lesions were observed. 2-YEAR STUDY IN RATS: Groups of 60 male and 60 female rats received 3,4-dihydrocoumarin in corn oil by gavage at age at doses of 0, 150, 300, or 600 mg/kg body weight. After 15 months, up to 10 animals from each group were evaluated. Survival, Body Weights, and Clinical Findings: Survival rates of dosed male rats were lower than that of the controls (O mg/kg, 28/51; 150 mg/kg, 12/50; 300 mg/kg, 8/50; 600 mg/kg, 2/50) but survival rates of dosed female rats were similar to that of the controls (31/50, 21/51, 26/50, 23/51). The decreased survival in dosed male rats was attributed to a chemical-related increase in the severity of nephropathy. The final mean body weight of male rats receiving 600 mg/kg was lower than that of the controls, but the final mean body weights of other dosed groups of male rats and all dosed groups of female rats were similar to those of the controls. No clinical findings related to chemical administration were observed. Hematology and Clinical Chemistry: At the 15-month interim evaluation, the hemoglobin concentrations, mean erythrocyte volumes, or mean erythrocyte hemoglobin concentrations in the 300 and 600 mg/kg female rats were slightly, but significantly, lower than those of the controls. In males, only the hemoglobin concentration in the 600 mg/kg group was significantly lower. Serum levels of alkaline phosphatase, alanine aminotransferase, sorbitol dehydrogenase, or g-glutamyltransferase in the 300 and 600 mg/kg male rats were significantly higher than those in the controls. In females, alkaline phosphatase and g-glutamyltransferase levels were significantly higher in the 600 mg/kg group. Pathology Findings: The principal lesions associated with the administration of 3,4-dihydrocoumarin to rats occurred in the kidney and forestomach. There was a chemical related increase in the severity of nephropathy in all dosed male rats and in 300 and 600 mg/kg female rats. There was a corresponding increased incidence of parathyroid gland hyperplasia, probably as a result of compromised renal function. In the standard evaluation of single kidney sections, renal tubule adenomas were observed in one 150 and two 600 mg/kg males and one each in the control, 150, and 300 mg/kg females. Transitional cell carcinomas were also observed in two 600 mg/kg male rats. However, an extended evaluation of step sections identified significantly higher incidences of focal hyperplasia and adenoma in the 600 mg/kg males than in controls (hyperplasia: 0/50, 5/48, 6/47, 8/50; adenoma: 1/50,1/48, 3/47, 6/50). The incidence of forestomach ulcers in all groups of dosed male rats was significantly greater than that of the controls (4/47, 14/48, 20/50, 16/46). STOP-EXPOSURE EVALUATION: A group of 40 male rats received 600 mg/kg 3,4-dihydrocoumarin in corn oil by gavage for 9 months, when 20 of the animals were necropsied and evaluated. The remainder of the male rats received only the corn oil vehicle until they died or until the end of the study. Similarly, a group of 30 male rats received 600 mg/kg 3,4-dihydrocoumarin in corn oil by gavage for 15 months, when 10 of the rats were necropsied and evaluated. The remaining 20 rats received only corn oil until the end of the study. A group of 20 vehicle control male rats was necropsied at 9 months, and another 10 vehicle control male rats were necropsied at 15 months. The severity of nephropathy in male rats of the stop-exposure groups was significantly greater than that of males examined at the 9- and 15-month interim evaluations. This was expected because nephropathy is a progressive degenerative disease that naturally increases in severity with age. 2-YEAR STUDY IN MICE: Groups of 70 male and 70 female mice received 3,4-dihydrocoumarin in corn oil by gavage at doses of 0, 200, 400, or 800 mg/kg body weight. After 15 months, five to 10 animals from each group were evaluated. Additional groups of 8 to 10 animals were evaluated for clinical pathology after 15 months. Survival, Body Weights, and Clinical Findings Survival rates of dosed male and female mice were similar to those of the controls (males: O mg/kg, 42/50; 200 mg/kg, 39/51; 400 mg/kg, 34/51; 800 mg/kg, 38/50; females: 36/51, 39/50, 41/50, 28/52). Final mean body weights of dosed male and female mice were similar to those of the controls. No clinical findings were noted that were related to chemical administration. Hematology and Clinical Chemistry: There were no differences in hematology or clinical chemistry parameters that were considered to be chemical related. Pathology Findings: The principal neoplasms associated with the administration of 3,4-dihydrocoumarin to mice occurred in the liver. There were significantly increased incidences of hepatocellular adenomas in all groups of dosed female mice. Further, the incidences of multiple hepatocellular adenomas in dosed female mice were greater than that of the controls (control, 0/51; 200 mg/kg, 6/50; 400 mg/kg, 9/50; 800 mg/kg, 9/52). However, there was no corresponding increased incidence of hepatocellular carcinoma in dosed female mice (3/51, 2/50, 4/50, 6/52), and the incidences of hepatocellular adenoma or carcinoma were similar between dosed and control male groups (adenoma: 29/50, 23/51, 36/51, 31/50; carcinoma: 11/50, 11/51, 11/51, 6/50). The incidence of alveolar/bronchiolar adenoma in the 200 and 400 mg/kg male mice was marginally greater than that of the controls (8/50,15/50,15/51,10/50). However, these neoplasms were not considered chemical related because the increased incidence was slight and there was no corresponding increased incidence in the 800 mg/kg group. The incidence of alveolar/bronchiolar neoplasms in female mice was similar between the dosed and control groups (adenoma: 2/51, 5/50, 1/48, 3/51; carcinoma: 0/51, 1/50, 0/48, 0/51). In the standard evaluation of single sections of kidney, focal hyperplasia and adenoma or carcinoma of the renal tubule were identified in several dosed male mice, but not in controls [adenoma or carcinoma (combined): 0/50,1/51, 2/51,1/49; hyperplasia: 2/50, 2/51, 5/51, 2/49]. In an extended evaluation of step sections, a few additional males with focal hyperplasia or renal tubule adenomas were identified in the dosed groups. However, the incidences of these lesions in dosed groups of male mice were not significantly greater than those of the controls, and did not increase with dose (hyperplasia: 0/50,1/51, 3/51, 1/49; renal tubule adenoma: 0/50, 0/51, 2/51, 1/49). Therefore, the low number of renal tubule neoplasms in male mice was not considered to be chemical related. GENETIC TOXICOLOGY: 3,4-Dihydrocoumarin did not induce gene mutations in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without exogenous metabolic activation (S9). It induced sister chromatid exchanges but not chromosomal aberrations in cultured Chinese hamster ovary cells, with and without S9. No induction of micronuclei was noted in peripheral blood erythrocyte samples obtained from male and female B6C3F1 mice at the end of the 13-week toxicology study. CONCLUSIONS: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activity of 3,4-dihydrocoumarin in male F344/N rats based on increased incidences of renal tubule adenomas and focal hyperplasia. The transitional cell carcinomas in two 600 mg/kg males may also have been chemical related. There was no evidence of carcinogenic activity of 3,4-dihydrocoumarin in female F344/N rats receiving 150, 300, or 600 mg/kg. There was no evidence of carcinogenic activity of 3,4-dihydrocoumarin in male B6C3F1 mice receiving 200, 400, or 800 mg/kg. There was some evidence of carcinogenic activity in female B6C3F1 mice based on increased incidences of hepatocellular adenoma and hepatocellular adenoma or carcinoma (combined). 3,4-Dihydrocoumarin caused ulcers, hyperplasia, and inflammation of the forestomach, parathyroid gland hyperplasia, and increased severity of nephropathy in male rats. Synonyms: 1,2-benzodihydropyrone, 2H-1-benzopyran-2-one, 2-chromanone, 3,4-dihydro-2H-1-benzopyran-2-one, dihydrocoumarin, hydrocoumarin, o-hydroycinnamic acid, delta-lactone-hydrocinnamic acid, melilotin, melilotine, melilotol, 2-oxochroman

Journal Article↗
PubMed1993

NTP Toxicology and Carcinogenesis Studies of Coumarin (CAS No. 91-64-5) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Coumarin is the basic structure of numerous naturally occurring compounds with important and diverse physiological activities. More than a thousand coumarin derivatives have been described, varying from simple coumarins containing alkyl and hydroxyl side chains to complex coumarins with benzoyl, furanoyl, pyranoyl, or alkylphosphorothionyl substituents. Coumarin and 3,4-dihydrocoumarin were nominated by the Food and Drug Administration and the National Cancer Institute for study because of the widespread use of coumarin in perfumes, cosmetics, and other products as a fragrance, continued interest in coumarin compounds as flavor-enhancing agents for foods, and the interest in structure-activity relationships of this important group of compounds. Coumarin is believed to be metabolized to a 3,4-epoxide intermediate, which may be responsible for its toxic effects, while 3,4-dihydrocoumarin, which lacks the 3,4-double bond, is not considered likely to form an epoxide intermediate. Toxicity and carcinogenicity studies were conducted by administering coumarin (97% pure) in corn oil by gavage to groups of male and female F344/N rats and B6C3F1 mice for 16 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, Drosophila melanogaster, and B6C3F1 mice. 16-DAY STUDY IN RATS: Groups of five male and five female rats received coumarin in corn oil by gavage at doses of 0, 25, 50, 100, 200, or 400 mg per kg body weight, 5 days a week for a total of 12 doses in a 16-day period. All female rats and four male rats receiving 400 mg/kg died. The mean body weight gains and final mean body weights of surviving dosed male and female rats were similar to those of the controls. There were no clinical signs of organ-specific toxicity, and there was no evidence of impaired blood coagulation from measurements of capillary clotting time or prothrombin and activated partial thromboplastin time. 16-DAY STUDY IN MICE: Groups of five male and five female mice received coumarin in corn oil by gavage at doses of 0, 40, 75, 150, 300, or 600 mg per kg body weight, 5 days a week for a total of 12 doses in a 16-day period. All mice receiving 600 mg/kg, two male mice receiving 300 mg/kg, and one male mouse receiving 75 mg/kg died. The mean body weight gains and final mean body weights of surviving dosed male and female mice were similar to those of the controls. Clinical findings of inactivity, excessive lacrimation, piloerection, bradypnea, ptosis, or ataxia were observed in some mice from the 300 and 600 mg/kg groups within the first several hours after dosing. Capillary clotting time and platelet counts of dosed mice were similar to those of controls. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats received coumarin in corn oil by gavage at doses of 0,19, 38, 75,150, or 300 mg per kg body weight. Three male and three female rats receiving 300 mg/kg died. The mean body weight gains and final mean body weights of male rats that received 150 and 300 mg/kg were significantly lower than those of the controls. There were no clinical signs related to specific organ toxicity. Male and female rats receiving coumarin exhibited dose-related decreases in mean erythrocyte volume and mean erythrocyte hemoglobin, and dose-related increases in erythrocyte counts. Serum levels of total bilirubin and one or more cytoplasmic enzymes including alanine aminotransferase, aspartate aminotransferase, ornithine carbamoyltransferase, and/or sorbitol dehydrogenase in males and females receiving 300 mg/kg were higher than those of controls. The absolute and relative liver weights of male and female rats that received 150 and 300 mg/kg were significantly greater than those of the controls. Centrilobular hepatocellular degeneration and necrosis, chronic active inflammation, and bile duct hyperplasia were observed in the liver of rats receiving 150 or 300 mg/kg. The high dose selected for the 2-year study was 100 mg/kg, which was just below the level at which mortality, lower final mean body weiody weights, and treatment-related liver lesions were observed in the 13-week study. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice received coumarin in corn oil by gavage at doses of 0, 19, 38, 75, 150, or 300 mg per kg body weight. Two male mice receiving 300 mg/kg died. The mean body weight gain and final mean body weight of surviving male mice that received 300 mg/kg were significantly lower than those of the controls. No clinical signs of toxicity were observed. Male and female mice receiving coumarin exhibited dose-related decreases in mean erythrocyte volume and mean erythrocyte hemoglobin. The absolute and relative liver weights of males and females that received 150 and 300 mg/kg were significantly greater than those of the controls. Centrilobular hepatocellular hypertrophy was observed in male and female mice receiving 300 mg/kg. The high dose selected for the 2-year study was 200 mg/kg, which was just below the level at which mortality and liver lesions were observed in the 13-week study. 2-YEAR STUDY IN RATS: Groups of 60 male and 60 female rats were administered coumarin in corn oil by gavage at doses of 0, 25, 50, or 100 mg per kg body weight. After 15 months, 10 animals from each group were evaluated. Survival, Body Weights, and Clinical Findings: None of the male rats receiving 100 mg/kg and only two males receiving 50 mg/kg survived until the end of the study (vehicle control, 28/50; 25 mg/kg, 9/50; 50 mg/kg, 2/51; 100 mg/kg, 0/50). Survival of dosed female rats was similar to that of the controls (29/50, 38/50, 36/50, 30/50). The reduced survival in dosed male rats was primarily attributed to chemical-related exacerbation of spontaneously occurring renal disease. Final mean body weights of female rats that received 100 mg/kg and all dosed groups of male rats were lower than those of the controls. There were no clinical signs of toxicity in rats, other than nonspecific signs relating to debilitation as a result of renal or other spontaneous disease. Hematology and Clinical Chemistry: At the 15-month interim evaluation, the values for one or more hematologic parameters including mean erythrocyte volume, mean erythrocyte hemoglobin in 50 and 100 mg/kg rats, and hematocrit or hemoglobin in 100 mg/kg rats were significantly lower than those of controls. Activated partial thromboplastin times were also significantly lower in 50 and 100 mg/kg males, while platelet counts were significantly higher. Activities of alanine aminotransferase, sorbitol dehydrogenase, or g-glutamyltransferase in 50 and 100 mg/kg male and 100 mg/kg female rats were significantly higher than those of the controls at the 15-month interim evaluation. Pathology Findings: The principal lesions associated with the administration of coumarin to rats for up to 2 years occurred in the liver, kidney, and forestomach. While the hepatic lesions were seen in all groups of males, they occurred only in the 50 and 100 mg/kg females. The lesions consisted of a spectrum of changes including hepatocellular necrosis, fibrosis, cytologic alteration, and increased severity of bile duct hyperplasia. The incidences of hepatocellular neoplasms were not increased in dosed rats. There was a chemical-related increase in the average severity of nephropathy in all groups of dosed male and female rats. There were corresponding increased incidences of parathyroid gland hyperplasia in all groups of dosed males, probably as a result of compromised renal function. In the standard evaluation of single kidney sections, a low incidence of renal adenomas was seen in all groups of males and in 100 mg/kg females (males: vehicle control, 1/49; 25 mg/kg, 2/50; 50 mg/kg, 2/51; 100 mg/kg, 1/50; females: 0/49, 0/50, 0/50, 2/49). An evaluation of step sections identified additional individuals with renal tubule focal hyperplasia (males: 2/49, 12/50, 10/51, 6/50; females: 1/49, 0/50, 4/50, 2/49) and adenoma (males: 0/49, 4/50, 5/51, 4/50; females: 0/49, 0/50, 1/50,1/49) in the dosed groups. The incidences of forestomach ulcers in all groups of dosed male rats and in 100 mg/kg female rats were significantly greater than those of the controls (males: 7/48, 24/50, 35/51, 34/50; females: 1/48, 1/49, 6/50, 9/48). STOP-EXPOSURE EVALUATION: A group of 40 male rats received 100 mg/kg coumarin in corn oil by gavage for 9 months, when 20 of the animals were necropsied and evaluated. The remainder of the male rats received only the corn oil vehicle during the 15-month recovery period. Similarly, a group of 30 male rats received 100 mg/kg coumarin in corn oil by gavage for 15 months, when 10 of the rats were necropsied and evaluated. The remaining 20 rats received only corn oil during the 9-month recovery period. A group of 20 vehicle control male rats were necropsied at 9 months, and another 10 vehicle control male rats were necropsied at 15 months. While chemical-related hepatic lesions were seen at both the 9- and 15-month interim evaluations, the incidences and severities of these lesions following the recovery period were generally similar to controls. Thus, the hepatic lesions produced by 9 or 15 months of exposure were reversible. In contrast to the liver lesions, the severity of nephropathy in male rats following the recovery period was significantly greater than that of males examined at the 9- and 15-month interim evaluations. This is not unexpected, since nephropathy is a progressive degenerative disease that naturally increases in severity with age. The incidence of renal tubule hyperplasia in the 15-month stop-exposure group (dosed for 15 months followed by the recovery period) and the incidence of renal tubule adenoma in the 9-month stop-exposure group were significantly greater than those of the control group. 2-YEAR STUDY IN MICE: Groups of 70 male and 70 female mice were administered coumarin in corn oil by gavage at doses of 0, 50, 100, or 200 mg per kg body weight for up to 2 years. After 15 months, 19 or 20 mice from each group were evaluated. Survival, Body Weights, and Clinical Findings: Survival of dosed male and female mice was similar to that of the controls (males: vehicle control, 43/50; 50 mg/kg, 47/50; 100 mg/kg, 42/50; 200 mg/kg, 37/51; females: 33/50, 40/50, 42/51, 28/51). The mean body weights of 200 mg/kg male and female mice were lower than those of controls throughout much of the study. There were no clinical findings related to chemical administration. Hematology and Clinical Chemistry: Mean erythrocyte volume, mean erythrocyte hemoglobin, and hematocrit of 200 mg/kg males and mean erythrocyte volume of 200 mg/kg females were significantly lower than those of the controls. Blood platelet counts of 200 mg/kg males and females were significantly higher than those of controls. There were no biologically significant differences in enzyme activities between dosed and control mice. Pathology Findings: The principal toxic lesions associated with the administration of coumarin to mice occurred in the liver. The incidences of centrilobular hypertrophy in 100 and 200 mg/kg males and 200 mg/kg females were significantly greater than those of controls. The incidences of syncytial alteration in all male dose groups and in 200 mg/kg females were also significantly greater than controls. The incidences of eosinophilic foci, a putative preneoplastic lesion, and of hepatocellular adenoma were significantly greater in the 50 and 100 mg/kg females. Hepatocellular carcinomas occurred with low incidences in the dosed females, but none occurred in the controls. The overall incidence of hepatocellular neoplasms (benign and malignant combined) in the 50 and 100 mg/kg females (control, 8/50; 50 mg/kg, 27/49; 100 mg/kg, 31/51; 200 mg/kg, 13/50) exceeds the range in historical controls (range 2%-34%; 129/898, 14.4%) from recent NTP studies. The reason for a lack of liver response in 200 mg/kg female mice is not known, but may be due in part to the decrease in body weight. While the incidences of eosinophilic foci were marginally greater in dosed male mice, the incidences of hepatocellular neoplasms were similar among the dosed and control groups. The incidences of alveolar/bronchiolar adenomas were significantly greater in 200 mg/kg male and female mice than in the controls. Further, the incidence of alveolar/bronchiolar carcinoma in 200 mg/kg females was also significantly greater than in controls. The overall incidence of pulmonary neoplasms (benign and malignant combined) in the 200 mg/kg groups (males: 14/50, 9/50,15/50, 25/51; females: 2/51, 5/49, 7/49, 27/51) exceeds the range in historical controls (males: range 6%-28%; 166/900, 18.4%; females: range 0%-14%; 58/899, 6.5%) from recent NTP studies. The incidence of squamous cell papilloma of the forestomach in 50 mg/kg males was greater than that of the controls (2/50, 8/50, 2/50, 0/51) and also exceeds the range of this neoplasm in control male mice from recent NTP studies (range 0%-14%; 27/902, 3.0%). The incidence of squamous cell papilloma of the forestomach in 50 mg/kg female mice was also slightly increased (1/52, 5/50, 2/51, 2/51); however, the incidence did not exceed the NTP historical range (27/901, 3%; range, 0%-10%). GENETIC TOXICOLOGY: Coumarin induced gene mutations in Salmonella typhimurium strain TA100 in the presence, but not in the absence, of exogenous metabolic activation (S9); no mutations were induced in strains TA98, TA1535, or TA1537, with or without S9. In Chinese hamster ovary cells, coumarin induced sister chromatid exchanges in the absence of S9, and chromosomal aberrations in the presence of S9. Coumarin did not induce sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster treated either as adults by feeding or injection, or as larvae by feeding. No increase in the frequency of micronucleated erythrocytes was observed in peripheral blood of male and female B6C3F1 mice administered coumarin by gavage for 13 weeks. CONCLUSIONS: Under the conditions of these 2-year gavage studies there was some evidence of carcinogenic activity of coumarin in male F344/N rats based on increased incidences of renal tubule adenomas. There was equivocal evidence of carcinogenic activity of coumarin in female F344/N rats based on a marginally increased incidence of renal tubule adenomas. There was some evidence of carcinogenic activity of coumarin in male B6C3F1 mice based on the increased incidence of alveolar/bronchiolar adenomas. There was clear evidence of carcinogenic activity of coumarin in female B6C3F1 mice based on increased incidences of alveolar/bronchiolar adenomas, alveolar/bronchiolar carcinomas, and hepatocellular adenomas. The marginally increased incidences of squamous cell papillomas of the forestomach in male and female mice receiving 50 mg/kg may have been related to coumarin administration. The administration of coumarin to rats was also associated with an increased severity of nephropathy in the kidney and of bile duct hyperplasia in the liver, increased incidences of ulcers of the forestomach, and necrosis, fibrosis, and cytologic alteration of the liver. Administration of coumarin to mice was also associated with centrilobular hypertrophy, syncytial alteration, and eosinophilic focus in the liver. Synonyms: 5,6-benzo-alpha-pyrone, 2H-1-benzopyran-2-one, 2H-benzolblpyran-2-one, 1,2-oxo-1,2-benzopyran, 1,2-benzopyrone, cis-o-coumarinic acid lactone, coumarinic anhydride, cumarin, o-hydroxycinnamic acid lactone, kumarin, [2-propenoic acid, 3-(-2-hydroxyphenyl)-delta-lactone], Rattex, tonka bean camphor

Journal Article↗
PubMed1993

NTP Toxicology and Carcinogenesis Studies of Benzyl Acetate (CAS No. 140-11-4) in F344/N Rats and B6C3F1 Mice Feed Studies).

Benzyl acetate is used as a flavoring agent in foods, as a fragrance in soaps and perfumes, as a solvent for cellulose acetate and nitrate, and as a component of printing inks and varnish removers. The NTP previously studied the toxicology and carcinogenicity of this chemical in F344/N rats and B6C3F1 mice using the gavage route of administration and corn oil as a vehicle. Benzyl acetate increased the incidences of pancreatic acinar cell adenomas in male rats and the incidences of hepatocellular adenomas and forestomach neoplasms in male and female mice. Because of the confounding effect of corn oil on the incidences of pancreatic neoplasms and because of controversy over the use of the gavage route of administration, the NTP decided to restudy benzyl acetate using the dosed feed route of administration. In these repeat studies, male and female F344/N rats and B6C3F1 mice received benzyl acetate (at least 98% pure) in feed for 13 weeks and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium nunnery, cultured Chinese hamster ovary cells, LS178Y mouse lymphoma cells, Drosophila melanogaster, and mouse bone marrow and peripheral blood cells. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were fed diets containing 0, 3,130, 6,250,12,500, 25,000, or 50,000 ppm (0, 230, 460, 900,1,750, or 3,900 mg/kg body weight for males and 0, 240, 480, 930,1,870, or 4,500 mg/kg for females) benzyl acetate for 13 weeks. Nine male and nine female rats receiving 50,000 ppm benzyl acetate died or were killed moribund between weeks 2 and 8 of the study. The mean body weight gain and the final mean body weight of 25,000 ppm males were significantly lower (P</=0.01) than those of the control group. Feed consumption by exposed rats, except the 25,000 and S0,000 ppm males and 50,000 ppm females, was similar to that by the controls. The reduced feed consumption by 25,000 and 50,000 ppm males and 50,000 ppm females may have been due to toxicity or decreased palatability. Tremors and ataxia occurred only in the 50,000 ppm rats. These findings were first observed on day 15 in nine males and six females and continued until the end of the study. Cholesterol levels in 12,500 and 25,000 ppm females and triglyceride levels in 25,000 ppm females were lower than those in the controls. Chemical-related lesions occurred in the brain, kidney, tongue, and skeletal muscles of the thigh. Necrosis of the brain involving the cerebellum and/or hippocampus, degeneration and regeneration of the renal tubule epithelium, and degeneration and sarcolemma nuclear hyperplasia of the tongue and skeletal muscles occurred in most male and female 50,000 ppm rats. This effect was observed in the 1,000 mg/kg group in the previous gavage study (NTP, 1986). 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were fed diets containing 0, 3, 130, 6,250, 12,500, 25,000, or 50,000 ppm (0, 425, 1,000, 2,000, 3,700, or 7,900 mg/kg body weight for males and 0, 650, 1,280, 2,980, 4,300, or 9,400 mg/kg for females) benzyl acetate. One 50,000 ppm male mouse died and one 50,000 ppm female mouse was killed moribund before the end of the study. Mean body weight gains and final mean body weights of all exposed male and female mice were significantly lower than those of the controls and the mean body weight gains decreased with increased exposure level. Feed consumption by 3,130 ppm males and all exposed females was lower than that by the controls. Tremors occurred only in females and were first observed on day 16 in three females receiving 50,000 ppm, day 94 in one female receiving 25,000 ppm, and day 93 in one female receiving 12,500 ppm. The tremors continued until the end of the study. Necrosis of the brain involving the hippocampus occurred in four 50,000 ppm mice, one male and three females. Hepatocellular necrosis also occurred in the male with brain lesions. On reexamination of the previous 13-week gavage study (NTP, 1986), a similar lesion was seen in the brain of one 1,000 mg/kg female mouse; none were seen in 1,000 mg/kg male mi male mice. The lesion was less severe than that described in the present dosed feed study. The highest dose used in the gavage study was 1,000 mg/kg compared to an estimated high dose of 7,200 mg/kg for the feed study. 2-YEAR STUDY IN RATS: The doses selected for the 2-year feed study of benzyl acetate in F344/N rats were based on lower survival, mean body weights, and feed consumption, and on increased incidences of histopathologic brain lesions in 50,000 ppm male and female rats in the 13-week study. Groups of 60 male and 60 female F344/N rats were fed diets containing 0, 3,000, 6,000, or 12,000 ppm benzyl acetate for 2 years. Survival, Body Weights, Feed and Compound Consumption, and Clinical Pathology: Survival of exposed rats was similar to that of the controls. The mean body weights of the 12,000 ppm males and exposed females were approximately 5&percnt; lower than those of the controls throughout most of the study. The feed consumption by 12,000 ppm males was slightly lower than that by the controls. Dietary levels of 3,000, 6,000, and 12,000 ppm benzyl acetate were estimated to result in average daily consumption levels of 130, 260, and 510 mg/kg body weight (males) and 145, 290, and 575 mg/kg (females). No biologically significant changes in hematology or clinical chemistry parameters were found that could be attributed to benzyl acetate administration. Pathology Findings: No compound-related increased incidences of neoplasms or nonneoplastic lesions occurred in male or female F344/N rats receiving benzyl acetate for as long as 2 years. 2-YEAR STUDY IN MICE: The doses selected for the 2-year feed study of benzyl acetate in B6C3F1 mice were based primarily on lower body weight gains and lower final mean body weights of exposed mice in the 13-week study. Groups of 60 male and 60 female B6C3F1 mice were fed diets containing 0, 330, 1,000, or 3,000 ppm benzyl acetate for 2 years. Survival, Body Weights, Feed and Compound Consumption, and Clinical Pathology: Survival of all exposed mice, except the 3,000 ppm females, was similar to that of the control groups. Survival of 3,000 ppm females was significantly higher than that of the control group. Throughout the 2-year study, the mean body weights of 1,000 and 3,000 ppm males and females were 2&percnt; to 14&percnt; lower than those of the control groups. Dietary levels of 330, 1,000, and 3,000 ppm benzyl acetate were estimated to result in average daily consumption levels of 35, 110, and 345 mg/kg (males) and 40, 130, and 375 mg/kg (females). No biologically significant changes in hematology or clinical chemistry parameters were observed in mice receiving 330,1,000, or 3,000 ppm benzyl acetate. Pathology Findings: No increase in neoplasm incidence in mice could be attributed to benzyl acetate administration in feed. This contrasts with the previous finding that administration of benzyl acetate in corn oil by gavage once daily 5 days a week for as long as 2 years was carcinogenic to mice, causing increased incidences of hepatocellular neoplasms and forestomach neoplasms. The contrast in results between the two studies may be due to differences in the dose levels used (highest dose: gavage, 1,000 mg/kg a day; feed, 360 mg/kg a day). Dose-related increased incidences or severities of nonneoplastic nasal lesions occurred in the most posterior portions of the nasal cavity in all exposed groups. The lesions occurred in the majority of the exposed mice and consisted of atrophy and degeneration, primarily of the olfactory epithelium, cystic hyperplasia of the nasal submucosal glands, pigmentation of the mucosal epithelium, and exudate accumulation. GENETIC TOXICOLOGY: Benzyl acetate was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537, with or without exogenous metabolic activation (S9). However, a positive response was observed for benzyl acetate, with and without S9, in the mouse lymphoma assay for induction of trifluorothymidine resistance in L5178Y cells. No significant increases in the frequencies of sister chromatid exchanges or chromosomal aberrations occurred in cultured Chinese hamster ovary cells treated with benzyl acetate in vitro, with or without S9, and no increases in either sister chromatid exchanges or chromosomal aberrations occurred in bone marrow cells of male mice treated in vivo by intraperitoneal injection. No increase in sex-linked recessive lethal germ cell mutations occurred in male Drosophila melanogaster administered benzyl acetate in feed or by injection. Tests of benzyl acetate for induction of micronucleated erythrocytes in bone marrow and peripheral blood of mice were also negative. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of benzyl acetate in male or female F344/N rats receiving 3,000, 6,000, or 12,000 ppm; however, rats may have tolerated higher doses. There was no evidence of carcinogenic activity of benzyl acetate in male or female B6C3F1 mice receiving 330, 1,000, or 3,000 ppm. Nasal lesions associated with benzyl acetate exposure in male and female mice included nasal mucosa atrophy and degeneration (primarily of the olfactory epithelium), cystic hyperplasia of the nasal submucosal gland, and luminal exudate and pigmentation of the nasal mucosal epithelium. In previous 2-year gavage studies (TR-250), benzyl acetate increased the incidence of acinar cell adenomas of the exocrine pancreas in male F344/N rats; the gavage vehicle may have been a contributing factor. There was no evidence of carcinogenic activity in female F344/N rats receiving 250 or 500 mg/kg a day. There was some evidence of carcinogenic activity in male and female B6C3F1 mice, indicated by the increased incidences of hepatocellular adenomas and squamous cell neoplasms of the forestomach. Synonyms: acetic acid benzyl ester, acetic acid phenyl methyl ester, (acetoxymethyl)benzene, acetoxytoluene, benzyl ethanoate, phenylmethyl acetate

Journal Article↗
PubMed2003

NTP toxicology and carcinogenesiss studies of citral (microencapsulated) (CAS No. 5392-40-5) in F344/N rats and B6C3F1 mice (feed studies).

UNLABELLED: Citral is used primarily as lemon flavoring in foods, beverages, and candies. It is also used as a lemon fragrance in detergents, perfumes, and other toiletries. Citral was nominated by the National Cancer Institute for study because of its widespread use in foods, beverages, cosmetics, and other consumer products and its structure as a representative beta-substituted vinyl aldehyde. Male and female F344/N rats and B6C3F1 mice were exposed to microencapsulated citral (greater than 96% pure) in feed for 14 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, mouse bone marrow cells, and mouse peripheral blood erythrocytes. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were fed diets containing starch microcapsules with a load of 31.3% citral. The concentration of citral in the diet was 3,900, 7,800, 15,600, or 31,300 ppm microencapsulated citral (equivalent to average daily doses of approximately 345, 820, 1,785, and 1,585 mg citral/kg body weight to males and 335, 675, 1,330, and 2,125 mg/kg to females) for 14 weeks. Additional groups of 10 male and 10 female rats received untreated feed (untreated controls) or feed containing placebo microcapsules (vehicle controls). In the second week of the study, all rats in the 31,300 ppm groups were killed moribund. Mean body weights of exposed males and females that survived to the end of the study were generally significantly less than those of the vehicle controls. Feed consumption by 15,600 and 31,300 ppm males and females was less than that by the vehicle controls during the first week of the study. Males and females in the 31,300 ppm groups exhibited listlessness, hunched posture, absent or slow paw reflex, and dull eyes. Exposure of rats to citral may have been associated with forestomach epithelial hyperplasia and hyperkeratosis, bone marrow atrophy and hemorrhage, and nephrotoxicity. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were fed diets containing 3,900, 7,800, 15,600, or 31,300 ppm microencapsulated citral (equivalent to average daily doses of approximately 745, 1,840, 3,915, and 8,110 mg/kg to males and 790, 1,820, 3,870, and 7,550 mg/kg to females) for 14 weeks. Additional groups of 10 male and 10 female mice received untreated feed (untreated controls) or feed containing placebo microcapsules (vehicle controls). In the second week of the study, four males in the 31,300 ppm group were killed moribund. Mean body weights of all exposed groups of males and females were significantly less than those of the vehicle controls. Feed consumption by females exposed to 7,800 ppm or greater was less than that by the vehicle controls during the first week of the study. By the end of the study, feed consumption by all exposed groups was greater than that by the vehicle controls. Mice in the 15,600 and 31,300 ppm groups were generally thin and lethargic; a few males in the 7,800 ppm group were also thin. The incidences of ovarian atrophy were significantly increased in females exposed to 15,600 or 31,300 ppm. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female F344/N rats were fed diets containing 1,000, 2,000, or 4,000 ppm microencapsulated citral for 2 years. Additional groups of 50 male and 50 female rats received untreated feed (untreated controls) or feed containing placebo microcapsules (vehicle controls). Dietary concentrations of 1,000, 2,000, and 4,000 ppm delivered average daily doses of approximately 50, 100, and 210 mg/kg to males and females. Survival of all exposed groups of males was significantly greater than that of the vehicle control group. Mean body weights of rats exposed to 4,000 ppm were generally less than those of the vehicle controls from week 49 (males) or 25 (females) to the end of the study. Feed consumption by exposed groups was similar to that by the vehicle controls. No neoplasms or nonneoplastic lesions were attributed to exposure to citral. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female B6C3F1 mice were fed diets containing 500, 1,000, or 2,000 ppm microencapsulated citral for 2 years. Additional groups of 50 male and 50 female mice received untreated feed (untreated controls) or feed containing placebo microcapsules (vehicle controls). Dietary concentrations of 500, 1,000, and 2,000 ppm delivered average daily doses of approximately 60, 120, and 260 mg/kg to males and females. Survival of exposed males and females was similar to that of the vehicle control groups. Mean body weights of mice exposed to 1,000 or 2,000 ppm were generally less than those of the vehicle controls throughout the study, and mean body weights of 500 ppm females were less from week 30 to the end of the study. Feed consumption by the exposed groups was similar to that by the vehicle controls. The incidences of malignant lymphoma occurred with a positive trend in female mice, and the incidence in 2,000 ppm females was significantly greater than that in the vehicle control group. Tissues most commonly affected by malignant lymphoma were the spleen, mesenteric lymph node, thymus, and, to a lesser extent, the ovary. GENETIC TOXICOLOGY: Citral was not mutagenic in S. typhimurium strain TA98, TA100, TA1535, or TA1537 with or without induced rat or hamster liver S9 enzymes. In cytogenetic tests with cultured Chinese hamster ovary cells, citral induced sister chromatid exchanges with and without S9, but chromosomal aberrations were not significantly increased after exposure to citral, with or without S9. Negative results were obtained in an in vivo bone marrow micronucleus test in male B6C3F1 mice treated by intraperitoneal injection with 250 to 750 mg/kg daily for 3 days. Likewise, no increases in the frequencies of micronucleated erythrocytes were observed in peripheral blood samples collected from male and female mice within 24 hours of the final exposure in the 14-week study. In conclusion, citral gave negative results in in vitro and in vivo tests for genotoxicity, with the exception of the in vitro mammalian cell test for sister chromatid exchange induction CONCLUSIONS: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of citral in male or female F344/N rats exposed to 1,000, 2,000, or 4,000 ppm. There was no evidence of carcinogenic activity of citral in male B6C3F1 mice exposed to 500, 1,000, or 2,000 ppm. There was equivocal evidence of carcinogenic activity in female B6C3F1 mice based on increased incidences of malignant lymphoma.

Acyclic Monoterpenes↗
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 d-Carvone (CAS No. 2244-16-8) in B6C3F1 Mice (Gavage Studies).

d-Carvone occurs naturally in caraway and dill seeds and in many essential oils; it has been used as a carminative and in perfumes and soaps. Toxicity and carcinogenesis studies were conducted by administering d-carvone (approximately 96% pure) in corn oil by gavage to groups of male and female B6C3F1 mice for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Chinese hamster ovary (CHO) cells. Sixteen-Day Studies: All mice that received 1,600 or 3,500 mg/kg died within 7 days. Relative liver weights were increased for dosed male mice, and relative thymus weights were decreased for dosed female mice. No compound-related lesions were observed. Thirteen-Week Studies: All male mice and 9/10 female mice that received the top dose of 1,500 mg/kg died before the end of the studies. No compound-related histopathologic changes were observed. Based on survival at the high doses in the 13-week studies, 2-year NTP Toxicology and Carcinogenesis studies were conducted by administering d-carvone in corn oil by gavage to groups of 50 male and 50 female mice at doses of 375 or 750 mg/kg, 5 days per week for 103 weeks. Two-Year Studies: Mean body weights of dosed and vehicle control mice were similar throughout the studies. Survival of dosed male mice was similar to that of vehicle controls (vehicle control, 37/50; low dose, 42/50; high dose, 36/50); survival of dosed female mice was greater than that of vehicle control female mice (14/50; 29/50; 38/50). Apparently, abscesses in the urogenital system caused the early deaths of many vehicle control female mice. No neoplastic lesions attributed to d-carvone dosing were observed in mice. Genetic Toxicology: d-Carvone was not mutagenic in S. typhimurium but induced sister chromatid exchanges and chromosomal aberrations in CHO cells. Conclusions: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of d-carvone for male or female B6C3F1 mice administered 375 or 750 mg/kg, 5 days per week for 2 years. Synonyms for d-carvone: (+)-carvone; d(+)-carvone; (S)-carvone; (S)-(+)carvone; (S)-2-methyl-5-(1-methylethenyl)-2-cyclohexen-1-one; (S)-d-p-mentha-6-8,(9)-dien-2-one; (S)-(+)-p-mentha-6,8-dien-2-one; d-1-methyl-4-isopropenyl-6-cyclohexen-2-one. Carvol is a synonym for carvone (d, l not specified)

Journal Article↗
PubMed1986

NTP Toxicology and Carcinogenesis Studies of Benzyl Acetate (CAS No. 140-11-4) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Benzyl acetate, a water-white liquid with a pear-like odor, is a natural constituent of several essential oils and flower absolutes extracted from jasmine, hyacinth, gardenia, tuberose, ylang-ylang, cananga, and neroli. Commercial benzyl acetate, a liquid prepared synthetically from benzyl chloride, acetic acid, and triethylamine is used primarily as a component of perfumes for soaps and as a flavoring ingredient. This compound is practically insoluble in water but is miscible in alcohol and ether and soluble in benzene and chloroform. Toxicology and carcinogenesis studies of benzyl acetate (>99% pure) were conducted by administering benzyl acetate in corn oil gavage to groups of 50 male and 50 female F344/N rats at doses of 0, 250, or 500 mg/kg body weight and to groups of 50 male and 50 female B6C3F1 mice at doses of 0, 500, or 1,000 mg/kg once daily five days per week for 103 weeks. Dose selection for the 2-year study was based on mean body weight gain depression and decreased survival observed at higher doses in 13 week studies. The absence of any observable adverse effect of benzyl acetate on the survival or mean body weight gains of the rats or mice in the 2-year studies suggests that both the rats and the mice of each sex could have tolerated higher doses. An infection in the genital tract was probably responsible for the deaths of 26/35 control, 14/32 low-dose, and 8/20 high-dose female mice before the end of the study. Acinar-cell adenomas in the pancreas of male rats occurred with a positive trend (P<0.01), and the incidence in the high-dose group (37/49, 76%) was significantly (P<0.01) higher than in the vehicle controls (22/50, 40%). The incidence of these tumors in the low-dose group (27/50, 54%) was comparable to that in the gavage controls. Acinar-cell hyperplasia of the pancreas was observed in 37/50 control, 34/50 low-dose, and 36/49 high-dose male rats. No acinar-cell hyperplasia or adenoma of the pancreas was observed in female rats. The incidence of retinopathy and cataracts in the high-dose male rats was increased compared with the controls (retinopathy: 1/50; 0/50; 20/50; cataracts: 0/50; 0/50; 13/50). Low-dose female rats had an increased incidence of retinopathy (18/50). Retinopathy and cataracts in rats have been associated with proximity to fluorescent light in this and previous studies. Preputial gland neoplasms occurred with a positive trend (P<0.05) in male rats (cystadenocarcinoma: 0/50; 0/50; 3/50; all adenocarcinoma: 0/50; 1/50; 4/50; adenocarcinoma or carcinoma combined: 1/50; 1/50; 6/50). However, the incidence of all preputial gland tumors was not significantly elevated (2/50; 1/50; 6/50). For female rats the incidence of clitoral gland neoplasms was marginally increased (2/50; 0/50; 5/50). Hepatocellular adenomas occurred in mice of each sex with statistically positive trends (males: 0/50; 5/49; 13/50; females: 0/50; 0/50; 6/50), and the incidences in the high-dose groups were greater than those in the controls (males: P<0.001; females: P<0.05). Hepatocellular carcinomas were marginally elevated in dosed male and high-dose female mice (males: 10/50; 14/49; 12/50; females: 1/50; 0/50; 4/50). Squamous cell papillomas or carcinomas of the forestomach (uncommon neoplasms) occurred with a positive trend (P<0.05) in male mice (4/49; 4/48; 11/49). The incidence of these tumors was also marginally (P=0.054) increased in the high-dose female mice (0/50; 0/50; 4/48). The incidences of these tumors in both the high-dose male and the high-dose female mice were considerably higher than the historical corn oil gavage control rates at this laboratory (males, 2/296, 0.7%; females, 2/297, 0.7%) and throughout the program (males, 14/1,070, 1.3%; females, 3/1,073, 0.3%). Forestomach hyperplasia occurred at increased incidences in dosed mice of either sex (males: 1/49, 7/48, 22/49; females: 1/50, 6/50, 17/48). The neoplasms and hyperplasia of the forestomach were probably related to administration of benzyl acetate. In a separate metabolism study, benzyl acetate was absorbed from the gastrointestinal traolism study, benzyl acetate was absorbed from the gastrointestinal tract of rats and mice, with approximately 90&percnt; of the administered dose recovered as various metabolites in the urine within 24 hr. The primary metabolite was hippuric acid, with minor amounts of a mercapturic acid, and one or more unidentified metabolites. This capacity for absorption, metabolism, and disposition was unaffected by the amount or number of doses administered. Benzyl acetate was not mutagenic in strains TA100, TA98, TA135, or TA137 of Salmonella typhimurium in the presence or absence of Aroclor 1254-induced Sprague-Dawley rat or Syrian hamster S9 when tested according to the preincubation protocol. Benzyl acetate did not induce sister-chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells in the presence or absence of Aroclor 1254-induced Sprague-Dawley rat liver S9. Benzyl acetate was mutagenic in the mouse lymphoma L5178Y/TK&plusmn; assay in the presence, but not in the absence, of Aroclor 1254-induced Fisher 344 rat liver S9. An audit was conducted on the experimental data and the draft technical report for these 2-year studies on benzyl acetate. Based on the results of this audit additional pathology examinations were conducted on all target organs in male rats and male and female mice. The Technical Report reflects these final pathology evaluations. The overall conclusions regarding the toxicology and carcinogenicity of benzyl acetate did not change as a result of this evaluation. Under the conditions of these gavage studies, benzyl acetate increased the incidence of acinar-cell adenomas of the exocrine pancreas in male F344/N rats; the gavage vehicle may have been a contributing factor. There was no evidence of carcinogenicity for female F344/N rats. For male and female B6C3F1 mice there was some evidence of carcinogenicity in that benzyl acetate caused increased incidences of hepatocellular adenomas and squamous cell neoplasms of the forestomach. Synonyms: alpha-acetoxytoluene; benzyl ethanoate; acetic acid, benzyl ester

Journal Article↗
PubMed1985

NTP Toxicology and Carcinogenesis Studies of Chlorobenzene (CAS No. 108-90-7) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Chlorobenzene is a colorless, volatile liquid under standard environmental conditions (vapor pressure=11.8 mm Hg at 25 degrees C, 760 mm Hg). It is used primarily as a solvent (e.g. resins, dyes, pesticides, and perfumes), a degreasing agent, and a chemical intermediate, particularly in the synthesis of nitrobenzenes. Although still considerable, estimates of the yearly production volume of chlorobenzene in the United States indicate declining use in recent years, due to the reduced demand for organochlorine pesticides utilizing chlorobenzene as an intermediate. Toxicology and carcinogenesis studies of chlorobenzene (<99% pure) were conducted by administering the test chemical in corn oil by gavage to groups of 50 male and 50 female F344/N rats and 50 female B6C3F1 mice at doses of 60 or 120 mg/kg. Groups of 50 male B6C3F1 mice received 30 or 60 mg/kg. Chlorobenzene was administered five times per week for 103 weeks. Groups of 50 rats and 50 mice of each sex received corn oil by gavage on the same schedule and served as vehicle controls, and additional groups of 50 rats and 50 mice of each sex served as untreated controls. The chlorobenzene doses were chosen on the basis of 90-day studies, in which doses 2-fold or greater in excess of the doses used in the 2-year study caused death, hepatocellular necrosis, renal tubular injury, thymic necrosis, or lymphoid or myeloid depletion of bone marrow, spleen or thymus. Mean body weights of dosed rats and mice were essentially the same or greater than those of the controls during the 2-year studies. Survivals of low dose male rats, dosed female rats, dosed male mice, and dosed female mice were not adversely affected by administration of chlorobenzene. Survival of high dose male rats in the 2-year study was significantly (P=0.033) lower than that of the vehicle controls. No chlorobenzene-induced toxic lesions responsible for this reduction in survival were observed. Based on the prechronic results and on the above data, the doses used in the 2-year study were considered to be adequate for carcinogenicity testing. Male rats dosed with chlorobenzene exhibited a significant (P<0.05) increase in the incidence of animals with neoplastic nodules of the liver (overall incidences: untreated control, 4/50 (8%); vehicle control, 2/50 (4%); low dose, 4/49 (8%); high dose, 8/49 (16)). Increased incidences of hepatocellular carcinomas in male rats or of neoplastic nodules or hepatocellular carcinomas in female rats were not observed. No increased tumor incidences were observed in female rats or in male or female mice. Under the conditions of these studies, chlorobenzene administration increased the occurrence of neoplastic nodules of the liver in high dose (120 mg/kg/day) male F344/N rats, providing some but not clear evidence of carcinogenicity of chlorobenzene in male rats. Carcinogenic effects of chlorobenzene were not observed in female F344/N rats or in male or female B6C3F1 mice. Levels of Evidence of Carcinogenicity: Male Rats: Equivocal Female Rats: Negative Male Mice: Negative Female Mice: Negative Synonyms: monochlorobenzene; chlorobenzol; phenyl chloride; benzene monochloride

Journal Article↗
PubMed1983

Carcinogenesis Studies of Allyl Isovalerate (CAS No. 2835-39-4) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Allyl isovalerate, a synthetic fragrance and flavoring ingredient in use since the 1950's, may be found in various products at the following concentrations: soap, 30 ppm; detergent, 3 ppm; creams, 15 ppm; perfume, 50 ppm; nonalcoholic beverages, 9 ppm; ice cream, 18 ppm; candy, 22 ppm; baked goods, 15-48 ppm; and gelatins and puddings, 1 ppm. A colorless liquid with an apple-like odor and taste, allyl isovalerate is approved by the U.S. Food and Drug Administration for use in foods. Specific production figures are not available, but U.S. production in 1980 exceeded 1,000 pounds. Carcinogenesis studies of allyl isovalerate (96% pure) were conducted by administering the test chemical in corn oil gavage to groups of 50 male and 50 female F344/N rats and to groups of 50 male and 50 female B6C3F1 mice at doses of 31 or 62 mg/kg. The doses selected were based on the chemically-induced toxic effects and depressed weight gains obtained from the 13-week studies. Doses were administered five times per week for 103 weeks. Groups of 50 rats and 50 mice of each sex received corn oil by gavage on the same dosing schedule and served as vehicle controls. Survival and mean body weight gain of rats of each sex and male mice were not adversely affected by the administration of allyl isovalerate. The significantly lower survival (P=0.001) and the lower mean body weight of low-dose female as compared with controls are likely consequences of the high incidence of a genital tract infection in the low-dose females. This infection was probably responsible for the deaths of 11/19 control, 22/33 low-dose, and 13/25 high-dose female mice that died before the end of the study. Squamous cell papillomas and epithelial hyperplasia of the nonglandular stomach were observed in dosed male mice in the 2-year studies (squamous cell papillomas: 0/50, 1/50, 2%, 3/48, 6%; epithelial hyperplasia: 1/50, 2%, 1/50, 2%, 7/48, 15%). The papillomas occurred with a significant positive trend (P<0.05). The incidence of high-dose male mice with squamous cell papillomas of the nonglandular stomach was also higher (P<0.01) than the historical rate for vehicle control male B6C3F1 mice in the Bioassay Program (5/881, 0.6%). Forestomach lesions were also observed in female mice: squamous cell papillomas (1/50, 0/50, 2/50) and epithelial hyperplasia of the nonglandular stomach (0/50, 2/50, 3/50). Pancreatic acinar-cell adenomas occurred at higher incidences in the dosed male rats than in the controls (control, 1/50, 2%; low-dose, 4/50, 8%; high-dose, 2/50, 4%). Pancreatic acinar-cell tumors were not observed in female rats. Preputial gland adenomas were observed in increased incidence in low-dose male rats (0/50, 4/50, 8%; P<0.05, 1/50, 2%). Mononuclear-cell leukemias in rats and lymphomas in mice occurred with increased incidences. This consistent dose-response increase among both rats and mice indicates that allyl isovalerate adversely affects the hematopoietic system. Cholangiofibrosis, nodular regeneration, cirrhosis, focal necrosis, fatty metamorphosis, and cytoplasmic vacuolization were observed at increased incidences in the livers of high-dose male and female rats in the 2-year study. No compound-related nonneoplastic lesions were observed in the mice of either sex. Liver neoplasms were not increased in either dosed rats or mice of either sex. Significant (P<0.05) decreases in tumor incidences were observed in male mice for hepatocellular carcinomas (18/50, 6/50, 9/50), for alveolar/bronchiolar adenomas or carcinomas (13/50, 6/50, 5/49), and for follicular-cell adenomas of the thyroid gland (5/47, 0/46, 1/49). Allyl isovalerate was not mutagenic for Salmonella typhimurium (tester strains TA 98, 100, 1535, and 1537) with or without metabolic activation. Under the conditions of these studies, allyl isovalerate was carcinogenic for F344/N rats and B6C3F1 mice, causing increased incidences of hematopoietic system neoplasms (mononuclear-cell leukemia in male rats and lymphoma in female mice). Levels of Evidence of Carcinogenicity: Male Rats: Positive Female Rats: Negativen female mice). Levels of Evidence of Carcinogenicity: Male Rats: Positive Female Rats: Negative Male Mice: Negative Female Mice: Positive

Journal Article↗
PubMed1987

NTP Carcinogenesis Studies of Food Grade Geranyl Acetate (71% Geranyl Acetate, 29% Citronellyl Acetate) (CAS No. 105-87-3) in F344/N Rats and B6C3F1 Mice (Gavage Study).

Geranyl acetate (3,7-dimethyl-2,6-octadiene-1-ol acetate) is a colorless liquid prepared by fractional distillation of selected essential oils or by acetylation of geraniol. It is a natural constituent of more than 60 essential oils, including Ceylon citronella, palmarosa, lemon grass, petit grain, neroli bigarade, geranium, coriander, carrot, and sassafras. Geranyl acetate is used primarily as a component of perfumes for creams and soaps and as a flavoring ingredient. On the U.S. Food and Drug Administration's list of substances "generally recognized as safe," the Food Chemicals Codex (1972) specifies that geranyl acetate must contain at least 90% total esters. Carcinogenesis studies of food-grade geranyl acetate (containing approximately 29% citronellyl acetate) were conducted by administering the test chemical in corn oil by gavage to groups of 50 male and 50 female F344/N rats at doses of 1,000 or 2,000 mg/kg body weight and to groups of 50 male and 50 female B6C3F1 mice at doses of 500 or 1,000 mg/kg. Doses were administered five times per week for 103 weeks. Groups of 50 rats and 50 mice of each sex received corn oil by gavage on the same dosing schedule and served as vehicle controls. The cumulative toxicity of geranyl acetate in the 2-year study was indicated by the significantly shorter survival of high dose male rats (control, 34/50; low dose, 29/50; high dose, 18/50) and of high dose male mice (control, 31/50; low dose, 32/50; high dose, 0/50) and of dosed female mice (38/50; 15/50; 0/50) when compared with controls. Throughout most of the 2-year study, mean body weights of high dose rats and mice of each sex were lower than those of the controls. The occurrence of retinopathy or cataracts in the high dose male rats and low dose female rats as compared with the controls does not appear to be related to the administration of geranyl acetate but rather the proximity of the rats to fluorescent light. The incidence of retinopathy or cataracts (combined) was: males: control, 0/50, 0%; low dose, 1/50, 2%; high dose, 11/50, 22%; females: control, 1/50, 2%; low dose, 13/50, 26%; high dose, 2/50, 4%. Kidney tubular cell adenomas, an uncommon tumor type, were found in 2/50 (4%) low dose male rats. The historical incidence of male corn oil gavage control F344/N rats with kidney tumors is 1/250 (0.4%) at this laboratory and 4/998 (0.4%) in the program. Squamous cell papillomas in the skin were increased marginally in low dose male rats (control, 0/50; low dose, 4/50, 8%; high dose, 1/50, 2%). In addition, one low dose male rat had a squamous cell carcinoma of the skin. The incidence of low dose male rats with either squamous cell papillomas or carcinomas was greater (P<0.05) in comparison with the controls. The historical incidence of squamous cell papillomas or carcinomas (combined) in gavage control male F344/N rats is 3.6% (9/250) at this laboratory and 2.5% (25/999) throughout the program. The incidence of all epidermal tumors was not significantly elevated in dosed male rats relative to controls (control, 3/50, 6%; low dose, 6/50, 12%; high dose, 1/50, 2%). All high dose (1,000 mg/kg) male and female mice were dead by week 91 as a result of accidentally being administered 2,800 mg/kg for 3 days during week 91; survival of low dose and control male mice was comparable. Survival of high dose male and dosed female mice may have been inadequate for the detection of late-appearing tumors. No evidence of any carcinogenic effect was found in either low or high dose mice of either sex. An infection of the genital tract was probably responsible for the deaths of 14/22 control and 8/32 low dose female mice before the end of the study. Cytoplasmic vacuolization was increased in the liver and in the kidney of male and female mice and was considered to be compound related (liver-- male: control, 1/50, 2%; low dose, 7/50, 14%; high dose, 47/50, 94%; female: 1/50, 2%; 27/50, 54%; 46/50, 92%; kidney or kidney tubule--male: 0/50; 0/50; 41/50, 82%; female: 0/50; 24/49, 49%; 37/50, 74%). Under the conditions of these studies, geranyl 4&percnt;; 46/50, 92&percnt;; kidney or kidney tubule--male: 0/50; 0/50; 41/50, 82&percnt;; female: 0/50; 24/49, 49&percnt;; 37/50, 74&percnt;). Under the conditions of these studies, geranyl acetate was not carcinogenic for F344/N rats or B6C3F1 mice of either sex; however, the reduced survival observed in high dose male rats, high dose male mice, and high and low dose female mice lowered the sensitivity of these studies for detecting neoplastic responses in these groups. In male rats the marginal increases of squamous cell papillomas of the skin and tubular cell adenomas of the kidney may have been related to administration of geranyl acetate. Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative Male Mice: Negative Female Mice: Negative

Journal Article↗
PubMed1982

Carcinogenesis Bioassay of Stannous Chloride (CAS No. 7772-99-8) in F344/N Rats and B6C3F1/N Mice (Feed Study).

Stannous chloride is an inorganic tin compound used as a food preservative, a stabilizer for colors, perfumes, and soaps, and as a reducing agent in tin plating. It is also used as a mordant in printing, a silvering agent for glass and plastics, a catalyst for curing phenolic resins, an additive to drilling muds, and an antisludge agent for oils. The chronic phase of a carcinogenesis bioassay for stannous chloride was conducted by feeding diets containing 1,000 or 2,000 ppm stannous chloride to groups of 50 F344/N rats and 50 B6C3F1/N mice of each sex for 105 weeks. Similar groups of untreated rats and mice served as controls. In this study, the concentrations of tin in bone, kidney, and liver were no higher than those attained in other lifetime studies utilizing 1/100 of the dose, suggesting that organ accumulation of tin was not dose dependent, but probably limited by absorption. Mean body weight gain and feed consumption of dosed and control rats and mice were comparable. Survival of high-dose male rats was somewhat lower than that of the control and low-dose groups (37/50, control; 39/50, low-dose; 30/50, high-dose). Survival of control male mice was less (P<0.05) than that of either dosed group (32/50, 42/50, 45/50); survival of the female mice appeared to be dose related (38/50, 33/50, 28/50). C-cell adenomas of the thyroid (2/50, 9/49, 5/50), C-cell adenomas or carcinomas combined (2/50, 13/49, 8/50), and adenomas of the lung (0/50, 0/50, 3/50) in male rats; and hepatocellular carcinomas or adenomas combined (3/49, 4/49, 8/49) and histiocytic malignant lymphomas (0/50, 0/49, 4/49) in female mice occurred with significant (P<0.05) positive trends and/or with significantly (P<0.05) increased incidences in the dosed groups when compared with the paired controls. However, when the lung adenomas in male rats are combined with lung carcinomas and when all lymphomas in female mice are considered, no statistical significance remains. For the thyroid C-cell tumors in male rats and for the liver tumors in female mice, the incidences in the high-dose groups were not significantly different from the historical control rates at that laboratory (C-cell tumors: 32/288, 11.1%; liver tumors: 24/297, 8%). When the historical control rate is used as a basis for comparison, the low-dose incidence of thyroid C-cell tumors remains significant (P<0.01). Under the conditions of this bioassay, stannous chloride was judged not to be carcinogenic for male or female F344/N rats or B6C3F1/N mice, although C-cell tumors of the thyroid gland in male rats may have been associated with the administration of the test chemical. Levels of Evidence of Carcinogenicity: Male Rats: Equivocal Female Rats: Negative Male Mice: Negative Female Mice: Negative

Journal Article↗
PubMed2003

[The quality of life in a Tunisian population of asthmatic patients].

Asthma is a chronic disease which disturb patient's quality of life (QL). The aim of our study is to evaluate the QL of 110 asthmatics patients aged from 18 to 70 years and the relationship between the QL and the severity of their asthma. We have used the "Chronic Respiratory Disease Questionnaire" translated in our arabic language and adapted to our tunisian environment. The asthmatic women was more affected then the asthmatic men at the environment dimension particularly when there were exposed to pollens, strong smells and perfumes (t < 0.003). QL was not influenced by age, disease's length and the education's level of the patients. Nevertheless, QL is more altered when asthma is more severe (p < 0.0005) and corticosteroids improve the QL for all the dimensions except the environment.

Adolescent↗