Glycogenic acanthosis of the esophagus.
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[The significance of acanthosis for external therapy].
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Ringworm with complicating acanthosis in swine.
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[On experimental acanthosis after local application of nicotinic acid esters].
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[Cytofluorometric study of nuclear DNA of basal cells in experimentally induced acanthosis].
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Acantholysis↗
NTP Toxicology and Carcinogenesis Studies of Triethanolamine (CAS No. 102-71-6) in F344 Rats and B6C3F1 Mice (Dermal Studies).
Triethanolamine is widely used as an ingredient in emulsifiers, thickeners, wetting agents, detergents, and alkalinizing agents in cosmetic products; as a chemical intermediate for anionic and nonionic surfactants and surface active agents in household cleaning agents, textiles, herbicides, pharmaceutical ointments, and other products; as a vulcanization accelerator in the manufacture of rubber; and in many other industrial applications. The National Cancer Institute nominated triethanolamine for study because of its widespread use in cosmetics and other consumer products, its high potential for worker exposure due to its many industrial uses, and its potential for conversion to the carcinogen N -nitrosodiethanolamine. Dermal application was chosen as the route of exposure to mimic the principal means of human exposure to triethanolamine and because considerable systemic exposure is achieved with this route. Male and female F344/N rats and B6C3F1 mice received triethanol amine (purity 98% or greater) by dermal application for 13 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, Drosophila melano gaster, and mouse peripheral blood erythrocytes. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were topically administered 0, 125, 250, 500, or 1,000 mg triethanolamine per kilogram body weight in acetone or 2,000 mg/kg neat triethanolamine, 5 days per week, for 13 weeks. All rats survived to the end of the study. Final mean body weights and weight gains of males and females administered 2,000 mg/kg and the mean body weight gain of females administered 1,000 mg/kg were significantly less than those of the vehicle controls. Clinical observations included irritation, scaliness, and crustiness of the skin at the site of application for males and females. Males also had discoloration, and two males administered 2,000 mg/kg had ulceration at the site of application. Changes in clinical pathology parameters were minor and consistent with inflammation at the site of application. Kidney weights were generally greater in males and females administered 500, 1,000, or 2,000 mg/kg than in the vehicle controls. Microscopic lesions attributed to triethanolamine administration included acanthosis and inflammation at the site of application, nephropathy in females, and hypertrophy of the pituitary gland pars intermedia in males and females. These lesions generally occurred with dose-related increases in incidence and severity in males and females. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were topically administered 0, 250, 500, 1,000, or 2,000 mg triethanolamine per kilogram body weight in acetone or 4,000 mg/kg neat triethanolamine, 5 days per week, for 13 weeks. All mice survived to the end of the study. The final mean body weight and weight gain of males in the 250 mg/kg group were less than those of the vehicle controls. Clinical findings were observed only in mice in the 4,000 mg/kg groups and included scaliness, irritation, and discoloration at the site of triethanolamine application for males and females and skin erosion at this site in one male. The absolute kidney and liver weights of males and females administered 4,000 mg/kg were greater than those of the vehicle controls; relative kidney weights of males administered 1,000 mg/kg or greater and females in all dosed groups were also greater than those of the vehicle controls. Microscopic examination of the skin of dosed mice indicated acanthosis and inflammation at the site of application. Acanthosis occurred in all dosed groups and in one vehicle control female; the severity increased with increasing dose in males and females. Inflammation was observed in males and females in the 4,000 mg/kg groups and in one female in the 2,000 mg/kg group. 2-YEAR STUDY IN RATS: Based on the presence of acanthosis and inflammation at the site of application at the higher doses in the 13-week study, triethanolamine doses selected for the 2-year study in rats were 32, 63, and 125 mg/kg for malesr males and 63, 125, and 250 mg/kg for females. Groups of 60 male and 60 female rats were topically administered triethanolamine in acetone 5 days per week for 103 weeks. Ten male and ten female rats from each group were evaluated at 15 months for organ weights and histopathology. Survival, Body Weights, Clinical Findings, and Organ Weights: The survival rate of females in the 250 mg/kg group was slightly less than that of the vehicle controls. The mean body weight of females administered 250 mg/kg ranged from 9% to 12% less than that of the vehicle controls between weeks 73 and 93. Male and female rats receiving triethanolamine had irritated skin at the site of application; in dosed females, the site of application also had a crusty appearance. The number of animals in which these findings were observed increased with increasing dose. At the 15-month interim evaluation, the absolute left and right kidney weights and relative right kidney weight of females administered 250 mg/kg were significantly greater than those of the vehicle controls. Pathology Findings: The incidence of acanthosis at the site of application in males administered 125 mg/kg and the incidences of acanthosis, inflammation, and ulceration in dosed females were greater than in the vehicle controls at the 15-month interim evaluation and at the end of the 2-year study. Males in the 125 mg/kg group also had greater incidences of inflammation and ulceration than the vehicle controls, and females receiving 125 or 250 mg/kg had greater incidences of epidermal erosion than the vehicle controls at 2 years. There were no skin neoplasms at or away from the site of application that were considered related to treatment with triethanolamine. At the end of the study, renal tubule adenomas were observed in seven dosed males and in one vehicle control female and one female in the 63 mg/kg group. One male in the 125 mg/kg group and one female in the 250 mg/kg group had renal tubule hyperplasia. Extended (step-section) evaluation of the kidneys of all male rats revealed additional renal tubule adenomas in one vehicle control male, one male in the 32 mg/kg group, two males in the 63 mg/kg group, and three males in the 125 mg/kg group (including one male from the 15-month interim evaluation). An oncocytoma was also identified in one male in the 32 mg/kg group. Hyperplasia was identified in eight additional vehicle control males and in 19 additional dosed males. The total incidences (combined standard and extended evaluations) of renal tubule adenoma in dosed male rats were slightly greater than the vehicle control incidence (vehicle control, 1/50; 32 mg/kg, 2/50; 63 mg/kg, 6/49; 125 mg/kg, 4/50). The total incidence of hyperplasia in dosed and vehicle control males was similar (9/50, 8/50, 7/49, 6/50). The severity of hyperplasia in males in the 32 and 125 mg/kg groups was greater than that in the vehicle controls. 2-YEAR STUDY IN MICE: Based on dose-related inflammation at the site of application in the 13-week study, triethanolamine doses selected for the 2-year study in mice were 200, 630, and 2,000 mg/kg for males and 100, 300, and 1,000 mg/kg for females. Groups of 60 male and 60 female mice were topically administered triethanolamine in acetone 5 days per week for 103 weeks. Ten male and ten female mice from each group were evaluated at 15 months for organ weights and histopathology. Survival, Body Weights, Clinical Findings, and Organ Weights: Survival rates of all dosed groups of males and females were similar to those of the vehicle controls. The mean body weight of males administered 2,000 mg/kg ranged from 8% to 10% less than that of the vehicle controls from week 69 through the end of the study. Clinical findings included irritation and discoloration of the skin at the site of application for most males in the 2,000 mg/kg group and a few females in the 1,000 mg/kg group; males administered 200 or 630 mg/kg also had skin irritation. At the 15-month interim evaluation, the right kidney weights of male mice that received 630 or 2,000 mg/kg and the left kidney weights of males that received 2,000 mg/kg were significantly greater than those of the vehicle controls. Pathology Findings: Acanthosis and inflammation of the skin were observed at the site of application in male and female mice at the 15-month interim evaluation and at the end of the 2-year study. In males in the 2,000 mg/kg group, the incidences of both lesions were significantly greater than those in the vehicle controls at both time points; however, the severities of acanthosis and inflammation did not increase with dose. At the end of the study, the incidence of inflammation in females in the 1,000 mg/kg group was significantly greater than that in the vehicle controls. One vehicle control male and two males in each of the 630 and 2,000 mg/kg groups had ulcers at the site of application. At the 15-month interim evaluation, hepatocellular carcinomas were observed in dosed and vehicle control males and hepatocellular adenomas in dosed and vehicle control males and females; however, the incidences were not dose related. Nonneoplastic lesions observed at 15 months included foci of cellular alteration in a few dosed males and females; eosinophilic foci were also observed in two vehicle control females. At the end of the 2-year study, females in the 1,000 mg/kg group had significantly greater incidences of hepatocellular adenoma and multiple adenomas and a greater combined incidence of hepatocellular adenoma and carcinoma than the vehicle controls (adenoma: vehicle control, 22/50; 100 mg/kg, 22/50; 300 mg/kg, 24/50; 1,000 mg/kg, 40/50; multiple adenomas: 11/50, 9/50, 13/50, 29/50; combined adenoma and carcinoma: 23/50, 26/50, 28/50, 41/50). Females in the 300 mg/kg group had significantly greater incidences of hepatocellular carcinoma (1/50, 4/50, 7/50, 5/50) and eosinophilic foci (9/50, 10/50, 18/50, 16/50) than the vehicle controls. Incidences of hepatocellular adenoma and multiple adenomas in males in the 2,000 mg/kg group were significantly greater than those in the vehicle controls (adenoma: vehicle control, 27/50; 200 mg/kg, 27/50; 630 mg/kg, 29/50; 2,000 mg/kg, 37/50; multiple adenomas: 17/50, 18/50, 17/50, 29/50). Three males in the 2,000 mg/kg group had hepatoblastomas, and males in this group also had significantly greater incidences of hepatocellular neoplasms (combined) (adenoma, carcinoma, and hepatoblastoma: 31/50, 34/50, 33/50, 42/50) and eosinophilic foci (10/50, 17/50, 11/50, 23/50) than the vehicle controls. Male mice had a pattern of nonneoplastic liver lesions along with silver-staining helical organisms within the liver which suggested an infection with Helicobacter hepaticus. With polymerase chain reaction-based assays and culture, the presence of an organism compatible with H. hepaticus was confirmed. An increased incidence of hepatocellular neoplasms in male mice has been shown to be associated with H. hepaticus infection when hepatitis is also present. Therefore, interpretation of the increased incidence of hepatocellular neoplasms in mice was confounded. GENETIC TOXICOLOGY: Triethanolamine was not mutagenic in any of the in vitro or in vivo short-term tests performed by the NTP. It did not induce mutations in Salmonella typhimurium, and no induction of sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells exposed to triethanolamine was noted. These in vitro tests were conducted with and without S9 metabolic activation. Triethanolamine did not induce sex-linked recessive lethal mutations in germ cells of adult male Drosophila melanogaster exposed by feeding or injection. No increase in the frequency of micronucleated erythrocytes was observed in peripheral blood samples of male and female mice that received dermal applications of triethanolamine for 13 weeks. CONCLUSIONS: Under the conditions of these dermal studies, there was equivocal evidence of carcinogenic activity of triethanolamine in male F344/N rats based on a marginal increase in the incidence of renal tubule cell adenoma. There was no evidence of carcinogenic activity in female F344/N rats receiving 63, 125, or 250 mg triethanolamine per kilogram body weight. The study in male and female B6C3F1 mice was considered inadequate, because the presence of a Helicobacter hepaticus infection complicated inter pretation of the relationship between triethanolamine administration and liver neoplasms in these animals. Dosed rats and mice had varying degrees of acanthosis and inflammation, dosed rats had ulceration, and dosed female rats had epidermal erosion at the site of skin application. Synonyms: Nitrilo-2,2',2"-triethanol; 2,2',2"-nitrilotriethanol; 2,2',2"-nitrilotrisethanol; TEA; triaethanolamin-NG; triethanolamin; triethylolamine; tri(hydroxyethyl)amine; 2,2',2"-trihydroxytriethylamine; trihydroxytriethylamine; tris(hydroxyethyl)amine; tris(2-hydroxyethyl)amine; triethylolamine; trolamine Trade Names: Daltogen; Sterolamide; Thiofaco T-35
Journal Article↗
NTP Toxicology and Carcinogenesis Studies of Dimethoxane (CAS No. 828-00-2) (Commercial Grade) in F344/N Rats and B6C3F1 Mice (Gavage Studies).
Dimethoxane is used as an antimicrobial agent in water-based paints, dyestuffs, fabric softeners, sizings, and spinning emulsions. In the past, it was used in lipsticks and other cosmetic preparations. Toxicology and carcinogenesis studies were conducted by administering commercial-grade dimethoxane (80% pure, none of these impurities exceeded 3%) in corn oil gavage to groups of F344/N rats and B6C3F1 mice of each sex one time or 5 days per week for 16 days, 13 weeks, 15 months, or 2 years. Clinical pathology analyses were performed at 15 months in the 2-year studies. Commercial-grade dimethoxane was studied because that is the grade to which humans are generally exposed. The same lot of commercial-grade dimethoxane was used in genetic toxicology tests for mutagenicity in Salmonella typhimurium, for sister chromatid exchanges (SCEs) and chromosomal aberrations in Chinese hamster ovary (CHO) cells, and for sex-linked recessive lethal mutations and translocation in Drosophila. Sixteen-Day Studies: In the 16-day studies, rats and mice received 0, 125, 250, 500, 1,000, or 2,000 mg/kg dimethoxane in corn oil per day. Deaths occurred in rats and in male mice that received 2,000 mg/kg. Body weights of rats and mice were similar to those of vehicle controls. Compound-related clinical signs were not seen in surviving rats. Hemorrhage and necrosis of the stomach were observed in rats in the 2,000 mg/kg group which died before the end of the studies. Lesions of the forestomach, including inflammation, hyperplasia, hyperkeratosis, and ulceration, occurred in rats that received 250-2,000 mg/kg. Mice that received 500-2,000 mg/kg dimethoxane had lesions of the forestomach including erosion, ulceration, hyperplasia, and hyperkeratosis. Forestomach lesions were not seen at 125 or 250 mg/kg. Thirteen-Week Studies: No compound-related deaths occurred in rats. Doses used were 0, 31, 62, 125, 250, or 500 mg/kg dimethoxane in corn oil by gavage. The final mean body weights of rats that received 500 mg/kg were 17% lower than that of vehicle controls for males and 5% lower for females. Ulceration, inflammation, and acanthosis with hyperkeratosis of the stratified squamous epithelium of the forestomach were seen in rats that received 500 mg/kg. Forestomach lesions were not seen in males that received 31 mg/kg or in females that received 31, 62, or 125 mg/kg. All mice lived to the end of the studies (doses used were 0, 31, 62, 125, 250, or 500 mg/kg dimethoxane in corn oil by gavage). Final mean body weights of dosed and vehicle control mice were similar. Minimal-to- mild acanthosis and hyperkeratosis of the squamous epithelium of the forestomach were seen in 4/10 high dose male and 1/10 high dose female mice. Because of the forestomach lesions observed in rats and mice and reduced body weight observed for male rats, doses selected for the 2-year studies were 0, 62.5, or 125 mg/kg dimethoxane in corn oil, given by gavage 5 days per week to groups of 60 male rats; 0, 125, or 250 mg/kg to groups of 60 female rats; and 0, 250, or 500 mg/kg to groups of 58 or 60 mice of each sex. Ten animals per sex and species from each dose group were killed 15 months after initiation of the studies to determine toxicity, pre-neoplastic lesions, and early induced neoplasia. Fifteen-Month Studies: Minimal diffuse acanthosis and hyperplasia of the forestomach were seen in 7/10 female rats at 250 mg/kg, 7/10 males at 125 mg/kg, and 1/9 male and 1/9 female vehicle controls. Acanthosis of the forestomach was seen in 7/10 male and 6/10 female mice at 500 mg/kg. Harderian gland adenomas were seen in one high dose male and one high dose female mouse. A harderian gland adenocarcinoma was seen in a second high dose female mouse. No compound-related effects were observed for clinical chemical or hematologic values or for organ weights for rats or mice. Body Weight and Survival in the Two-Year Studies: Mean body weights of dosed and vehicle control rats and mice of each sex were generally similar. No significant differences in survival were observed between any groups of rated between any groups of rats (male: vehicle control, 23/50; low dose, 28/50; high dose, 21/50; female: 30/50; 31/50; 24/50) or mice (male: 33/50; 27/48; 29/50; female: 36/50; 35/50; 34/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: At no site was a significantly increased incidence of neoplastic lesions observed in dosed male or female rats or in dosed female mice. Acanthosis and hyperkeratosis were increased in the forestomach of high dose rats; acanthosis, hyperkeratosis, focal hyperplasia, and chronic active inflammation were increased in the forestomach of dosed mice. The incidence of squamous cell papillomas of the forestomach was increased in high dose male mice (vehicle control, 2/47; low dose, 3/47; high dose, 7/50). A squamous cell carcinoma of the forestomach was present in another high dose male mouse. Although the incidence of squamous cell papillomas in the high dose group was not significantly different from that in the vehicle controls, the incidence exceeded the highest observed in historical corn oil gavage vehicle controls (3/49). Other than a single squamous cell papilloma in the esophagus of a low dose male mouse, no hyperplastic or neoplastic lesions were seen outside the stomach of dosed mice which could be related to the administration of dimethoxane. Despite the observation of three harderian gland neoplasms in mice killed at 15 months, no increase in the incidences of harderian gland neoplasms was seen in dosed mice in the 2-year studies (male: 2/48; 2/48; 2/48; female: 2/48; 0/49; 2/50). Genetic Toxicity: Dimethoxane was mutagenic in strain TA100 of S. typhimurium in the presence but not the absence of exogenous metabolic activation; it was not mutagenic in strains TA98, TA1535, or TA1537 with or without activation. Dimethoxane induced SCEs and chromosomal aberrations in CHO cells both with or without exogenous metabolic activation. Dimethoxane induced sex-linked recessive lethal mutations in Drosophila when administered by abdominal injection to adult males; no induction of reciprocal translocations was observed in adult males after injection of dimethoxane. Conclusions: Under the conditions of these 2-year corn oil gavage studies, there was no evidence of carcinogenic activity of dimethoxane for male F344/N rats receiving 62.5 or 125 mg/kg or for female F344/N rats receiving 125 or 250 mg/kg per day. There was equivocal evidence of carcinogenic activity of dimethoxane for male B6C3F1 mice, as indicated by an increased incidence of forestomach neoplasms. There was no evidence of carcinogenic activity for female B6C3F1 mice receiving 250 or 500 mg/kg per day. Acanthosis and hyperkeratosis occurred at increased incidences in the forestomach of high dose rats. Inflammation, acanthosis with hyperkeratosis, and focal hyperplasia occurred at increased incidences in the forestomach of dosed mice. Synonyms: acetomethoxan; acetomethoxane; 6-acetoxy-2,4-dimethyl-m-dioxane; 2,6-dimethyl-m-dioxan-4-yl acetate; 2,6-dimethyl-m-dioxan-4-ol acetate; 2,6-dimethyl-1,3-dioxan-4-ol acetate
Journal Article↗
[Effects of peeling agents (resorcinol, crystalline sulfur, salicylic acid) on the epidermis of guinea pig (author's transl)].
The mode of action of "classical peeling agents" such as resorcinol, crystalline sulfur, and salicylic acid on the epidermis is almost unknown. There are only a few experimental data available. Therefore the effects of resorcinol, crystalline sulfur, and salicylic acid were studied. A 1% and 3% concentration of these chemicals in vaselinum flavum or Unguentum Cordes was applied to the ears and flanks of adult male guinea pigs up to 14 days. Prior to biopsies at various time intervals, 3H-thymidine was injected intradermally. Specimens were paraffin embedded and routinely processed for autoradiographical analysis. The following parameters were assessed: Labelling index (L.I. in %); number of labelled basal cells per unit length of basement membrane; papillomatosis-index; and acanthosis-factor (projection histoplanimetry). The data were statistically analysed. The peeling agents induced a concentration-dependent increase of the L.I., acanthosis, and papillomatosis. Crystalline sulfur caused the most pronounced effect, followed by resorcinol. In contrast salicylic acid caused only a minute acanthosis factor and a slight increase in labelling. The correlation coefficient r of epidermal thickness to the L.I. for all concentrations and peeling agents used reaches the high figure of 0.978 for the ear. The 1% and 3% salicylic acid has a lower acanthosis factor than vaselinum flavum by itself. Preliminary autoradiographical studies in humans with 1% and 10% salicylic acid confirm these data. Salicylic acid counteracts acanthosis. These experiments show that crystalline sulfur and resorcinol have a potent effect on cell proliferation and acanthosis. They peel via proliferation hyperkeratosis. The mode of peeling by salicylic acid must be different, as cell proliferation and acanthosis are barely enhanced. The clinically known "keratolytic" effect of salicylic acid may be due to a direct action on the intercellular cement substance of the horny cells.
Animals↗
NTP Toxicology and Carcinogenesis Studies of 1,2-Dihydro-2,2,4-Trimethylquinoline (CAS No. 147-47-7) in F344/N Rats and B6C3F1 Mice (Dermal Studies) and the Dermal Initiation/Promotion Study in Female Sencar Mice.
1,2-Dihydro-2,2,4-trimethylquinoline (monomer) is used as an antioxidant in styrene-butadiene and nitrile-butadiene rubbers and latexes. It was nominated by the National Cancer Institute as part of a review of chemicals used in the manufacture and processing of rubber, during which potential occupational and consumer exposure to this compound can occur. It was selected for evaluation because it is a derivative of quinoline, a known rodent carcinogen, and was regarded as having potential carcinogenic activity. Because of the pattern of use and exposure, dermal administration was considered most appropriate. Male and female F344/N rats and B6C3F1 mice received topical applications of 1,2-dihydro-2,2,4-trimethylquinoline in acetone (greater than 90% pure) for 13 weeks or 2 years. Groups of female SENCAR mice received 1,2-dihydro-2,2,4-trimethylquinoline (greater than 90% pure) during a 1-year dermal initiation/promotion study to determine the tumor initiation or promotion potential of the chemical. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse peripheral blood cells. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were topically administered 0, 5, 20, 50, 100, or 200 mg 1,2-dihydro-2,2,4-trimethylquinoline/kg body weight in acetone, 5 days per week for 13 weeks. In addition, there were 10 male and 10 female untreated controls. All rats survived to the end of the study. Final mean body weights and mean body weight gains of treated male and female rats were similar to those of the vehicle controls except those of 200 mg/kg males, which were significantly lower than those of the vehicle controls. The only notable clinical observation was skin discoloration of treated rats. In the 200 mg/kg groups, absolute and relative liver weights of males and absolute liver weights of females were significantly greater than those of the vehicle controls. There were no significant differences in hematology or clinical chemistry parameters, reproductive tissue parameters, or estrous cycle characterization between treated and control groups. Histopathologic lesions of the skin at the site of application included acanthosis and hyperkeratosis in 100 and 200 mg/kg males and 200 mg/kg females. Cytoplasmic vacuolization of hepatocytes of mild to moderate severity was observed in the livers of all 200 mg/kg males and was considered treatment related. Based on the incidence and severity of skin and liver lesions observed in 200 mg/kg rats in the 13-week study, 100 mg/kg was selected as the high dose for the 2-year rat study. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were topically administered 0, 2.5, 5, 10, 20, or 50 mg 1,2-dihydro-2,2,4-trimethylquinoline/kg body weight in acetone, 5 days per week for 13 weeks. In addition, there were 10 male and 10 female untreated controls. All mice except one 2.5 mg/kg female survived to the end of the study. Final mean body weights and mean body weight gains of male and female mice were similar to those of the vehicle controls. There were no treatment-related clinical observations. There were no significant differences between treated and control groups in organ weights, hematology and clinical chemistry parameters, reproductive tissue parameters, or estrous cycle characterization. Histopathologic lesions of the skin at the site of application included acanthosis (epidermal hyperplasia), hyperkeratosis, and parakeratosis, all ranging from minimal to mild in severity. Minimal to mild fibrosis and subchronic inflammation were observed in the dermis. Based on the incidences and severities of skin lesions observed in 20 and 50 mg/kg mice in the 13-week study, 10 mg/kg was selected as the high dose for the 2-year mouse study. 2-YEAR STUDY IN RATS: Groups of 60 male and 60 female F344/N rats were topically administered 0, 36, 60, or 100 mg 1,2-dihydro-2,2,4-trimethylquinoline/kg body weight in acetone, 5 days per week for 103 (males) or 104 (females) weeks. Ten rats per group were evaluated after 15 moed after 15 months of treatment. Survival and Body Weights Survival of treated rats was similar to that of controls. Mean body weights of 60 mg/kg males and 100 mg/kg males and females were slightly lower than those of the controls after week 21. Mean body weights of 36 mg/kg males and females and 60 mg/kg females were generally similar to those of the controls throughout the study. Pathology Findings: No skin neoplasms were attributed to treatment with 1,2-dihydro-2,2,4-trimethylquinoline. Several nonneoplastic skin lesions were determined to be treatment related. Incidences of acanthosis at the site of application in all treated groups of males and in 100 mg/kg females at the 15-month interim evaluation were significantly greater than those in the controls. At the end of the 2-year study, incidences of acanthosis at the site of application in 60 and 100 mg/kg males and females and hyperkeratosis at the site of application in 60 mg/kg females were significantly greater than those in the controls. Absolute and relative right kidney weights of 60 and 100 mg/kg male rats were significantly greater than those of the controls at the 15-month interim evaluation. Incidences of renal tubule adenoma and adenoma or carcinoma (combined) in all treated groups of males were significantly greater than those in the controls. These incidences exceeded the range from the historical controls in 2-year NTP feed studies. An extended (step section) evaluation of the kidneys of male rats did not reveal an additional increase in neoplastic response because additional adenomas and hyperplasias were observed in the controls as well as in treated groups. 2-YEAR STUDY IN MICE: Groups of 60 male and 60 female B6C3F1 mice were topically administered 0, 3.6, 6, or 10 mg 1,2-dihydro-2,2,4-trimethylquinoline/kg body weight in acetone, 5 days per week for 103 (males) or 104 (females) weeks. Nine or ten mice per group were evaluated after 15 months of treatment. Survival and Body Weights: Survival of treated mice was similar to that of controls. Mean body weights of treated male and female mice were similar to those of the controls throughout the study. Pathology Findings: No neoplasms or nonneoplastic lesions were attributed to treatment with 1,2-dihydro-2,2,4-trimethylquinoline. 1-YEAR INITIATION/PROMOTION STUDY IN FEMALE SENCAR MICE: Groups of 30 female SENCAR mice were topically administered varying initiation/promotion treatments as outlined in the table below. Survival, Body Weights, and Clinical Findings: Survival in all treated groups was similar to that of the respective controls, except in the 2.5 mg 7,12-dimethylbenz(a)anthracene (DMBA)/0.5 mg 12-O-tetradecanoylphorbol-13-acetate (TPA) group in which survival was significantly lower than that of the controls. Mean body weights of all treated groups were similar to those of the respective controls throughout the study. No clinical observations were associated with 1,2-dihydro-2,2,4-trimethylquinoline treatment; however, mice promoted with TPA showed signs of irritation and papilloma at the site of application. Pathology Findings: Initiation and promotion with acetone alone was not associated with any skin lesions at the site of application. The incidences of acanthosis and chronic inflammation were increased in all groups promoted with TPA regardless of the initiator treatment; however, the incidences of nonneoplastic lesions were low in all other groups. Incidences of squamous cell papillomas and squamous cell carcinomas were markedly increased in the DMBA/TPA positive control group; however, no response was observed in groups initiated with DMBA and promoted with 5, 10, or 25 mg/kg 1,2-dihydro-2,2,4-trimethylquinoline or in the group initiated with 1,2-dihydro-2,2,4-trimethylquinoline and promoted with TPA. GENETIC TOXICOLOGY: 1,2-Dihydro-2,2,4-trimethylquinoline was not mutagenic in any of several strains of Salmonella typhimurium, with or without S9 metabolic activation. 1,2-Dihydro-2,2,4-trimethylquinoline induced sister chromatid exchanges in cultured Chinese hamster ovary cells in the absence of S9, but not in the presence of S9. However, no increase in the frequency of chromosomal aberrations was observed in cultured Chinese hamster ovary cells treated with 1,2-dihydro-2,2,4-trimethylquinoline, with or without S9. No increase in the frequency of micronucleated erythrocytes was noted in peripheral blood of male or female mice exposed topically to 1,2-dihydro-2,2,4-trimethylquinoline for 13 weeks. CONCLUSIONS: Under the conditions of these 2-year dermal studies, there was some evidence of carcinogenic activity of 1,2-dihydro-2,2,4-trimethylquinoline in male F344/N rats, based on increased incidences of renal tubule adenoma and adenoma or carcinoma (combined). There was no evidence of carcinogenic activity of 1,2-dihydro-2,2,4-trimethylquinoline in female F344/N rats receiving 36, 60, or 100 mg/kg, or in male or female B6C3F1 mice receiving 3.6, 6, or 10 mg/kg. Exposure of rats to 1,2-dihydro-2,2,4-trimethylquinoline by dermal application in acetone for 2 years resulted in acanthosis in males and females and hyperkeratosis in females at the site of application. No nonneoplastic lesions in male or female mice were attributed to treatment with 1,2-dihydro-2,2,4-trimethylquinoline. Synonyms: 2,2,4-Trimethyl-1,2-dihydroquinoline; acetone anil; methylquinoline Trade names: Agerite Resin D; Flectol A; Flectol H; Flectol Pastilles; Vulkanox HS/LG; Vulkanox HS/Powder
Journal Article↗
Toxicology and Carcinogenesis Studies of 4-Vinyl-1-cyclohexene Diepoxide (CAS No. 106-87-6) in F344/N Rats and B6C3F1 Mice (Dermal Studies).
4-Vinyl-1-cyclohexene diepoxide is used a chemical intermediate and as a reactive diluent for diepoxides and epoxy resins. Toxicology and carcinogenesis studies were conducted by administering 4-vinyl-1-cyclohexene diepoxide (97% pure) in acetone by dermal application to individually housed F344/N rats and B6C3F1 mice for 14 days, 13 weeks, 15 months, and 2 years. Additional studies included evaluation of immune function after a 5-day dermal exposure and evaluation of the oral toxicity of 4-vinyl-1-cyclohexene diepoxide in 16-day and 13-week corn oil gavage studies. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse L5178Y lymphoma cells, and Chinese hamster ovary (CHO) cells. Fourteen-Day Dermal Studies: In the 14-day studies, all rats that received 924 mg/kg or higher (equivalent to 139 mg/rat or higher for males and 112 mg/rat of higher for females) died before the end of the studies. Final mean body weights were lower than those of vehicle controls in males receiving 68 mg/rat and in females receiving 57 mg/rat. Excoriations on the skin at the application site were observed in the groups receiving 57 mg/rat or more. Males receiving 139 mg/rat and females receiving 112 mg/rat had congestion and/or hypoplasia of the bone marrow; most had acute nephrosis. Skin lesions, including epidermal necrosis and ulceration, epidermal hyperplasia, and hyperkeratosis, were found in the 139 and 112 mg/rat group; similar lesions of lesser severity were seen in the two lowest dose groups of each sex. All mice that received 1,787 mg/kg (equivalent to 43/mouse for males and 37 mg/mouse for females) and 3/5 male mice and 5/5 female mice that received 889 mg/kg (equivalent to 19-21 mg/mouse) died before the end of the 14-day dermal studies. Final mean body weights of exposed and vehicle control mice were generally similar. Lesions of the skin at the site of application were seen in 4/5 males and 4/5 females receiving 5 mg/mouse and all mice receiving 10 and 21 (males) or 19 (females) mg/mouse and included epidermal and sebaceous gland hyperplasia, hyperkeratosis, and ulceration. Thirteen-Week Studies: In the 13-week dermal studies, all rats survived to the end of the studies (doses up to 60 mg/rat). The final mean body weights of the 60 mg/rat groups were 9%-14% lower than those of the vehicle controls. Compound-related clinical signs in the 60 mg/rat groups observed during the second half of the studies included redness, scabs, and ulceration at the application site and burrowing behavior after dermal application. Hyperplasia of the sebaceous glands and acanthosis (hyperplasia) and hyperkeratosis of the squamous epithelium were seen at the site of application. In mice, no compound-related deaths occurred after applications of up to 10 mg/mouse in 13-week dermal studies, and final mean body weights of exposed and vehicle control mice were similar. Relative liver and kidney weights increased with dose. Compound-related lesions of the skin included sebaceous gland hyperplasia and acanthosis (hyperplasia) and hyperkeratosis of the stratified squamous epithelium at the site of application; ovarian atrophy was also considered to be compound related. In the 13-week oral studies, the major target organ of toxicity in rats and mice was the forestomach, as indicated by hyperkeratosis and hyperplasia of the stratified squamous epithelium. In female mice, ovarian atrophy was seen in 4-vinyl-1-cyclohexene diepoxide-dosed groups. Two-year studies were conducted by administering 4-vinyl-1-cyclohexene diepoxide in acetone by dermal application, 5 days per week for 105 weeks to groups of 60 rats of each sex at 0, 15, or 30 mg/animal. Groups of 60 mice of each sex were administered 0, 2.5, 5, or 10 mg/animal on the same schedule for 103 weeks. None of the doses selected had produced ulceration of skin in 13-week studies. Ten animals from each group were killed and examined during month 15 for toxicologic evaluation. Immune Function Studies: The immunotoxic effects of 4-vinyl-1-cyclohexene diepoxide were studied in male B6C3F1 mice in male B6C3F1 mice after a 5-day dermal exposure at doses ranging from 2.5 to 10 mg/mouse per day. 4-Vinyl-1-cyclohexene diepoxide was immunosuppressive at 10 mg/mouse and, to a lesser extent, at 5 mg/mouse, as indicated by a decrease in peripheral lymphocytes and the in vitro lymphoproliferative response to phytohemagglutinin and concanavalin A in the high dose group and suppression of the antibody plaque-forming-cell response in the 5 and 10 mg/mouse groups. Fifteen-Month Evaluation: Two of 10 male rats that received 30 mg had a squamous cell carcinoma of the skin at or adjacent to the site of application. Acanthosis was seen in exposed rats (mild severity at 30 mg/rat and minimal severity at 15 mg/rat); hyperkeratosis was observed for rats in the 30 mg/rat groups. Compound-related nonneoplastic skin lesions in mice included acanthosis, hyperkeratosis, and sebaceous gland hyperplasia/hypertrophy. Squamous cell papillomas and carcinomas were seen in mice that received 5 or 10 mg/mouse; none was seen in vehicle control or low dose groups (papillomas--male: mid dose, 1/10; high dose, 2/10; female: 1/10; 1/10; carcinomas-- male: 2/10; 8/10; female: 2/10; 5/10). One vehicle control and all exposed female mice had atrophy of the ovary. Hyperplasia of the ovarian surface epithelium was seen in 8/10 females receiving 5 mg/mouse and 9/9 females receiving 10 mg/mouse. Two of nine females receiving 10 mg/mouse had granulosa cell tumors of the ovary, and 1/9 females receiving 10 mg/mouse had an ovarian papillary cystadenoma. Body Weights and Survival in the Two-Year Studies: In general, the body weights and survival were lower in mid and high dose groups than in vehicle controls. The survival was lower in exposed groups, primarily because of neoplasms (survival at week 105--male rats: vehicle control, 7/50; low dose, 8/50; high dose, 4/50; female rats: 27/50; 23/50; 15/50; male mice: vehicle control, 38/50; low dose, 35/50; mid dose, 4/50; high dose, 0/50; female mice: 30/50; 31/50; 15/50; 0/50). All high dose male mice died by week 83; the 10 surviving high dose female mice were killed during week 85. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Acanthosis and sebaceous gland hypertrophy of skin from the scapula or back were observed at substantially increased incidences in exposed male and female rats. Squamous cell papillomas in male rats and squamous cell carcinomas in male and female rats were observed only in exposed rats (squamous cell carcinomas--male: vehicle control, 0/50; low dose, 33/50; high dose, 36/50; female: 0/50; 16/50; 34/50). The incidences of basal cell adenomas or carcinomas (combined) were increased (male: 0/50; 1/50; 6/50; female: 0/50; 3/50; 4/50). For exposed mice, acanthosis, hyperkeratosis, and necrotizing inflammation of the skin were observed over the scapula or back. Squamous cell carcinomas were found only in exposed mice (male: vehicle control, 0/50; low dose, 14/50; mid dose, 39/50; high dose, 42/50; female: 0/50; 6/50; 37/50; 41/50). Follicular atrophy and tubular hyperplasia of the ovary in female mice were increased (atrophy: 12/50; 43/49; 47/50; tubular hyperplasia: 5/50; 35/49; 38/49; 34/50). Mid and high dose females had benign or malignant granulosa cell tumors (0/50; 0/49; 7/49; 12/50) and benign mixed tumors (0/50; 0/49; 11/49; 6/50). The combined incidences of luteomas, granulosa cell tumors, benign mixed tumors, or malignant granulosa cell tumors in mid and high dose female mice were increased (1/50; 0/49; 17/49; 18/50). The incidences of alveolar/bronchiolar adenomas or carcinomas (combined) in exposed female mice were marginally increased (4/50; 9/50; 11/50; 7/50). Genetic Toxicology: 4-Vinyl-1-cyclohexene diepoxide was mutagenic in S. typhimurium strains TA98, TA100, and TA1535 with and without exogenous metabolic activation; the compound was equivocally mutagenic in strain TA1537 without S9 but gave a positive response in the presence of activation. 4-Vinyl-1-cyclohexene diepoxide induced resistance to trifluorothymidine in mouse L5178Y/TK cells without exogenous metabolic activation; it was not tested with activation. 4-Vinyl-1-cyclohexene diepoxide induced sister chromatid exchanges and chromosomal aberrations in CHO cells in the presence and absence of exogenous metabolic activation. Conclusions: Under the conditions of these 2-year dermal studies, there was clear evidence of carcinogenic activity of 4-vinyl-1-cyclohexene diepoxide for male and female F344/N rats, as shown by squamous cell and basal cell neoplasms of the skin. There was clear evidence of carcinogenic activity of 4-vinyl-1-cyclohexene diepoxide for male and female B6C3F1 mice, as shown by squamous cell carcinomas of the skin in males and squamous cell carcinomas of the skin and ovarian neoplasms in females; increased incidences of lung neoplasms in females may also have been related to chemical application. Synonyms: 4-vinylcyclohexene diepoxide; 4-vinyl-1,2-cyclohexene diepoxide; 1-vinyl-3-cyclohexene diepoxide; 4-vinylcyclohexene dioxide; 1,2-epoxy-4-(epoxyethyl) cyclohexane; 1-epoxyethyl-3,4-epoxycyclohexane
Journal Article↗
Insulin resistance in obese adolescents.
The prevalence of obesity in adolescents is increasing rapidly. Obesity is associated with insulin resistance, which increases the risk for type 2 diabetes. We investigated insulin resistance in obese adolescents and its relationship to acanthosis nigricans. Height, weight and body mass index (BMI) were measured and each was expressed as a standard deviation score (SDS) based on national growth standards. Insulin resistance was estimated by using the homeostasis model assessment (HOMA-IR) score, calculated as fasting insulin (microU/mL) x fasting glucose (mmol/L)/22.5. Obese adolescents had significantly greater weight-SDS, BMI-SDS, fasting insulin levels, and HOMA-IR than did controls with normal weight. Acanthosis nigricans was present in 58.4% of obese adolescents. Fasting insulin levels and BMI-SDS were positively correlated with the degree of acanthosis nigricans (r = 0.383, P<0.0001 and r = 0.164, P < 0.05, respectively). On multiple regression analysis, HOMA-IR and BMI-SDS explained 16.8% of the degree of acanthosis nigricans (P<0.0001). Acanthosis nigricans thus may be a marker of insulin resistance and should be carefully looked for in obese adolescents.
Acanthosis Nigricans↗
Lipoatrophic diabetes.
A female patient with acanthosis nigricans, insulin resistant diabetes, and generalized lipoatrophy is reported. The patient developed skin pigmentation and acanthosis nigricans around the age of 34. Arthralgia, muscle weakness, and peripheral neuropathy were also present when she first visited us at 36 years of age. Dermatomyositis, systemic sclerosis, and internal malignancy were ruled out, and the diagnosis of acanthosis nigricans and insulin resistant diabetes was made. Her diabetes gradually worsened and, since the age of 39, she has been treated with an oral anti-diabetic drug. Around the age of 47, generalized lipoatrophy became prominent. Insulin receptor studies ruled out insulin resistant diabetes type A and B. At this point, we diagnosed this patient as having lipoatrophic diabetes, which is a syndrome characterized by insulin resistant diabetes, acanthosis nigricans, generalized lipoatrophy, and other metabolic disturbances. The control of her diabetes has been poor, and diabetic neuropathy and lipoatrophy-induced painful skin lesions such as clavus and tylosis have been persistent. The present case indicates the importance of careful skin examinations in the diagnosis of this syndrome.
Acanthosis Nigricans↗
[Nonalcoholic steatohepatitis in obese children: the prevalence and possible mechanism].
OBJECTIVE: To investigate the prevalence of nonalcoholic steatohepatitis (NASH) in obese children and its possible mechanism. METHODS: Three subgroups were classified according to their body mass index (BMI) in 123 obese children with BMI over 23 aged 7 to 16:34 cases with BMI> or =31 group; 57 cases with 25< or =BMI<30 group; 32 cases with 23< or =BMI<25 group. Ultrasonographic and biochemical parameters including serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), serum cholesterol, serum triglyceride, serum uric acid and free glucose to free insulin ratio (FGIR) were assayed. Twenty four children suspected as benign acanthosis nigricans underwent skin biopsy and its association with nonalcoholic steatohepatitis was also discussed. RESULTS: Ninety-nine children (80.49 %) showed abnormal hepatic sonograms and 54 were diagnosed as NASH with the prevalence of 43.90%. Compared with the other two groups, BMI> or =31 group was significantly higher in prevalence of abnormal hepatic sonograms, NASH, decreased FGIR and risk of benign acanthosis nigricans (P<0.01). Fifty-four children diagnosed as NASH showed significantly higher incidence of hyperlipidemia, insulin resistance and higher body mass index as compared with 24 subjects without fatty liver changes. In 54 NASH children, 20(37.04%) had benign acanthosis nigricans. By bivariate analysis, ALT and AST were correlated well with BMI, cholesterol, triglyceride and FGIR (r(s)=0.413, 0.290, 0.379, -0.477, P<0.01; r(s)=0.359, 0.349, 0.348, -0.369, P<0.01). CONCLUSION: There is a high prevalence of nonalcoholic steatohepatitis in simple obese children and high incidence of benign acanthosis nigricans in NASH subjects. BMI> or=30 is a high risk factor of being NASH. Severe disturbance of lipid metabolism and insulin resistance may be involved in the mechanism of NASH.
Acanthosis Nigricans↗
Evidence for heterogeneous pathogenesis of insulin-treated diabetes in black and white children.
OBJECTIVE: We have previously reported differences in the prevalence of beta-cell autoantibodies (AAs) in black and white children with insulin-treated diabetes, suggesting that the disease pathogenesis may be more heterogeneous among racial groups than previously thought. To further explore this issue, we compared clinical, biochemical, and autoimmune characteristics at disease diagnosis and follow-up treatment in an expanded number of black and white children with and without the presence of AAs. RESEARCH DESIGN AND METHODS: The study cohort of 130 black children and adolescents, aged <19 years, diagnosed with diabetes and treated with insulin at time of diagnosis (January 1979 to December 1998) were matched with an equal number of white children by age at onset, sex, and year of diagnosis. RESULTS: The black children had a higher prevalence of obesity (43 vs. 11%) and acanthosis nigricans (21 vs. 1%) than white children and a lower prevalence of AAs. Compared with black children who had AAs, those with no AAs were older and had a higher prevalence of obesity, acanthosis nigricans, and parental diabetes. However, one of four of the black children with AAs was obese and/or had acanthosis nigricans. Among white children, the absence of AAs was not associated with any differences in terms of obesity or acanthosis nigricans compared with those with AAs. Similar to their black counterparts, white children without antibodies were older and had a higher prevalence of parental diabetes. Although treatment with an insulin sensitizer was used, insulin therapy was rarely discontinued on follow-up. CONCLUSIONS: These pediatric subjects, irrespective of autoimmunity, often showed characteristics associated with type 2 diabetes. These characteristics were more frequently displayed in black than in white children. Our data suggest that childhood diabetes may constitute a spectrum of pathogenic mechanisms that may overlap, including those typically associated with both type 1 and type 2 diabetes. This finding could have therapeutic implications.
Adolescent↗
NTP technical report on the toxicity studies of Diethanolamine (CAS No. 111-42-2) Administered Topically and in Drinking Water to F344/N Rats and B6C3F1 Mice.
Diethanolamine is a high-production chemical used in cosmetics, in cutting fluids, as a dispersing agent for agricultural chemicals, and as an absorbent for acidic gases. Toxicology studies of diethanolamine were conducted in F344/N rats and B6C3F1 mice of both sexes for 2 weeks (5/sex/species/dose) and 13 weeks (10/sex/species/dose) to characterize and compare the effects of oral and dermal exposure. In addition to histopathology, evaluations included clinical pathology, urinalyses, and sperm morphology or vaginal cytology. In vitro genetic toxicity studies included assessments of mutagenicity in Salmonella typhimurium and mouse lymphoma L5178Y cells, analysis of chromosomal aberrations and sister chromatid exchange in Chinese hamster ovary cells, and determination of micronuclei formed in mice during the 13-week dermal exposure study. Groups of rats and mice received drinking water containing diethanolamine at concentrations of up to 10000 ppm during studies of 2 or 13 weeks duration. In the 2-week studies, rats and mice of both sexes received in the were 0, 630, 1250, 5000, and 10000 ppm diethanolamine in the drinking water. In the 13-week studies, rats received 0, 320, 630, 1250, 2500, and 5000 ppm (males) or 0, 160, 320, 630, 1250, and 2500 ppm (females) in drinking water; male and female mice received 0, 630, 1250, 2500, 5000, and 10000 ppm. All female rats in the 2 highest dose groups and 2 males in the 10000 ppm group in the 2-week study died before the end of the study. In the 13-week study, deaths of mice occurred in the 3 highest dose groups; 2 male rats in the top dose group also died. Surviving animals in the higher concentration groups in both studies exhibited depressed weight gains. Rats receiving diethanolamine developed a poorly regenerative, microcytic anemia in both studies. In the 2-week study, dosed male and female rats had increased kidney weights, renal tubular cell necrosis, and decreased renal function; rats in the 13-week study also showed increased incidences or severity of nephropathy, tubular necrosis, and mineralization. Degeneration of the seminiferous tubules of the testis was noted in dosed males in both the 2- and 13-week studies, and sperm motility and count were decreased in the 13-week study. Demyelination in the brain (medulla oblongata) and spinal cord was observed in male and female rats in the 13-week study. In mice, dose-dependent increases in liver weight were observed in males and females in the 2-week study; cytologic alteration and necrosis of individual hepatocytes were observed in the highest dose group. In the 13-week drinking water study in mice, nephropathy and tubular necrosis were observed in males, and degeneration of cardiac myocytes, and hepatocellular necrosis were seen in males and females. Cytologic alteration in the submandibular salivary gland was noted in male and female mice. Hepatocyte cytologic alteration also was noted in all dosed groups of mice. In the 2-week dermal studies, groups of rats and mice were administered daily doses of diethanolamine in 95% ethanol, ranging from 160 to 2500 mg/kg for mice, and from 125 to 2000 mg/kg for rats, 5 days per week. In 13-week studies, dermal doses ranged from 32 to 500 mg/kg for rats, and from 80 to 1250 mg/kg for mice. In the 2-week study, early deaths of male rats and male and female mice occurred in the highest dose groups and in female rats in the 2 highest dose groups (1000 and 2000 mg/kg). Body weight gains were reduced in rats and mice in the higher dose groups. Early deaths in the 13-week study were observed in the highest dose groups of rats (500 mg/kg) and mice (1250 mg/kg). Body weight gains were reduced in rats and mice given the higher doses. Rats in the dermal studies exhibited dose-dependent hematologic and renal function changes similar to those observed in rats in the drinking water study. In addition, in the 2-week study, rats exhibited ulcerative skin lesions at the site of application, accompanied by inflammatory cell infiltration, hyperkeratosis, and acanthosis (hyperplasia) of the epidermis.dermis. Hyperkeratosis, without ulceration, was observed in some animals. Ulceration at the site of application was observed in male and female mice. Acanthosis, without ulceration or inflammatory cell infiltration, was observed in mice in all lower dose groups. In the 13-week study, skin lesions at the site of application included ulceration and inflammation, hyperkeratosis, and acanthosis. Liver weights were increased in male and female rats, but there were no associated histopathological changes. Other treatment-related effects observed in rats included demyelination in the brain and spinal cord, and nephropathy, renal tubular necrosis, and/or tubular mineralization; mice exhibited cytological alterations in the liver and/or hepatocellular necrosis, renal tubular epithelial necrosis, and cardiac myocyte degeneration. In in vitro genetic toxicity studies, diethanolamine was not mutagenic in Salmonella typhimurium or mouse L5178Y TK± cells. Diethanolamine did not induce sister-chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells, nor did it induce micronuclei in peripheral blood erythrocytes in mice exposed by topical application for 13 weeks. All in vitro studies were conducted with and without S9 activation. Target organs of diethanolamine toxicity identified in these studies included bone marrow, kidney, brain, spinal cord, testis, and skin in rats, and liver, kidney, heart, salivary gland, and skin in mice. A no-observed-adverse-effect-level (NOAEL) was not achieved for hematological changes or nephropathy in rats (<160 ppm), or for cytologic alteration of the liver in mice (<630 ppm) in the drinking water studies. In the dermal studies, a NOAEL was not achieved for hematological changes, nephropathy, or hyperkeratosis of the skin in rats (<32 mg/kg), or for cytologic alteration of the liver or acanthosis of the skin in mice (<80 mg/kg). Synonyms: 2,2&vprime;-iminodiethanol; 2,2&vprime;-iminobisethanol; diethylolamine; bis(hydroxy-ethyl)amine; 2,2'dihydroxydiethylamine; 2,2&vprime;-aminodiethanol.
Journal Article↗
NTP Technical Report on the Toxicology and Carcinogenesis Studies of 2,4-Diaminophenol Dihydrochloride (CAS NO. 137-09-7) in F344/N Rats and B6C3F1 Mice (Gavage Studies).
2,4-Diaminophenol dihydrochloride is used in the manufacture of dyes and as a color accelerator in photographic developers. Toxicology and carcinogenesis studies were conducted by administering 2,4-diaminophenol dihydrochloride (greater than 97% pure) in corn oil by gavage to F344/N rats and B6C3F1 mice for 16 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse lymphoma cells, Drosophila melanogaster, and Chinese hamster ovary cells. 16-Day Studies: Groups of five rats of each sex received doses of 0, 6, 13, 25, 50, or 100 mg/kg and groups of five mice of each sex received doses of 0, 13, 25, 50, 100, or 200 mg/kg of 2,4-diaminophenol dihydrochloride in corn oil by gavage. There were no deaths among rats during the 16-day studies and chemical exposure had no effect on final mean body weights. Organ weight differences were unrelated to chemical exposure. Renal tubule necrosis was present in male and female rats in the 25, 50, and 100 mg/kg dose groups. All male and four female mice that received 200 mg/kg, all males and three females that received 100 mg/kg, and two female mice that received 50 mg/kg died before the end of the studies. Final mean body weights of surviving dosed mice were similar to controls. Absolute liver weights were increased in female mice that received 50 and 100 mg/kg and relative liver weights were increased in all female dose groups. Renal tubule necrosis was present in the 100 mg/kg male and female dose groups. 13-Week Studies: Groups of ten male and female rats received doses of 0, 12, 25, 50, 100, or 200 mg/kg and groups of ten male and female mice received doses of 0, 5, 9, 19, 38, or 75 mg/kg of 2,4-diaminophenol dihydrochloride in corn oil by gavage. All female and nine male rats that received 200 mg/kg and four males and one female in the 100 mg/kg rat groups died before the end of the studies. Final mean body weights of male rats that received 50 or 100 mg/kg were significantly lower than controls. Relative kidney weights were significantly increased in all male dose groups; absolute and relative kidney and liver weights were significantly increased in females that received 50 and 100 mg/kg. Lesions in rats associated with chemical exposure included renal tubule necrosis in males that received 25 mg/kg and above and in females that received 100 or 200 mg/kg. Forestomach ulcers with acanthosis and hyperkeratosis were present at 50 mg/kg and above in both sexes. Pigment, presumably 2,4-diaminophenol dihydrochloride or a metabolite, was present in the duodenum and within the renal tubule epithelium of all dose groups. Splenic lymphoid depletion was present in both sexes and bone marrow hyperplasia was present in groups of males that received 100 or 200 mg/kg. Hemosiderin was present in Kupffer cells of males that received 100 or 200 mg/kg. The severity of splenic extramedullary hematopoiesis increased with dose in males. There were no deaths among mice attributed to chemical exposure. Final mean body weight of male mice that received 75 mg/kg was 8% lower than for the controls. Absolute and relative liver weights were increased in males that received 9 mg/kg or above and in all female dose groups. Absolute and relative kidney weights of 38 and 75 mg/kg male mice and all dosed female mice were significantly increased. Absolute heart weights were increased in the 19, 38, and 75 mg/kg female groups. Lesions in 75 mg/kg mice included increased incidences of renal tubule regeneration; forestomach acanthosis and hyperkeratosis occurred in 38 and 75 mg/kg groups. Hemosiderin was present in the spleen of mice from all dose groups and in hepatic Kupffer cells of female mice that received 38 or 75 mg/kg. Pigment was present in the duodenum of males and females that received 9 mg/kg and above and in the renal tubule epithelium of both sexes that received 75 mg/kg. 2-Year Studies: The 2-year studies were conducted by administering 2,4-diaminophenol dihydrochloride in corn oil by gavage to groups of 60 male and 60 female F344/N rats and B6C3F1 mice. Tence. Ten animals from each dose group were evaluated after 15 months. Rats received doses of 0, 12.5, or 25 mg/kg; mice received doses of 0, 19, or 38 mg/kg. Body Weight and Survival in the 2-Year Studies: Mean body weights of high-dose male and female rats and of high-dose male mice were lower than those of the respective controls. Survival of dosed rats and mice was similar to controls throughout the 2-year studies. Neoplastic and Nonneoplastic Effects in the 2-Year Studies: The severity of nephropathy increased in high-dose male rats. The incidence of renal tubule cell hyperplasia was increased in rats that received 2,4-diaminophenol dihydrochloride; however, there were no renal tubule cell neoplasms attributed to chemical exposure. Renal tubule cell hyperplasia was present in three high-dose male mice and a renal tubule adenoma was present in one of the high-dose males with hyperplasia; two additional high-dose males also had renal tubule adenomas. These are uncommon neoplasms in male mice and were considered related to chemical exposure. In a supplemental review of step-sectioned kidneys, six additional hyperplasia were seen in high-dose male mice and adenomas in three other high-dose males. A tubule cell carcinoma was present in one low-dose female mouse. The incidences of several nonneoplastic kidney lesions, including necrosis and renal tubule regeneration, were also increased in male and female mice. Pigment was observed in the lamina propria of the duodenum, the submucosa of the forestomach, and in pancreatic and mesenteric lymph nodes in dosed rats. Hemosiderin was present in the renal tubule epithelial cells of low- and high-dose rats. The incidence of forestomach acanthosis was increased in dosed male mice and pigment was present in liver Kupffer cells, in the lamina propria of the duodenum, and in the mesenteric lymph nodes of male and female mice. Pigment and hemosiderin were also present in the renal tubule epithelium of dosed mice. Genetic Toxicology: 2,4-Diaminophenol dihydrochloride was mutagenic in the Salmonella typhimurium strain TA98 in the presence of exogenous metabolic activation (S9); it was not mutagenic in strain TA98 in the absence of S9, nor was it mutagenic in strains TA100, TA1535, or TA1537 with or without S9. 2,4-Diaminophenol dihydrochloride was positive in the mouse lymphoma assay for induction of trifluorothymidine resistance in L5178Y cells without S9; it was not tested with S9. No induction of sister chromatid exchanges or chromosomal aberrations was observed in Chinese hamster ovary cells treated with 2,4-diaminophenol dihydrochloride with and without S9. In the Drosophila melanogaster sex-linked recessive lethal assay, 2,4-diaminophenol dihydrochloride gave equivocal results when administered in the feed and negative results when administered by injection. Conclusions: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of 2,4-diaminophenol dihydrochloride in male or female F344/N rats that received 12.5 or 25 mg/kg. There was some evidence of carcinogenic activity of 2,4-diaminophenol dihydrochloride in male B6C3F1 mice based on increased incidences of renal tubule adenomas; there was no evidence of carcinogenic activity of 2,4-diaminophenol dihydrochloride in female B6C3F1 mice that received 19 or 38 mg/kg. Administration of 2,4-diaminophenol dihydrochloride to rats was associated with increased severity of nephropathy in males and females, increased incidence of nephropathy in females, and focal renal tubule hyperplasia in males and females. In mice, chemical exposure was associated with renal tubule necrosis and regeneration in males and females and forestomach acanthosis in males. Synonyms: Acrol, amidol, dianol
Journal Article↗
Genetic analysis of the insulin receptor gene in Chinese patients with extreme insulin resistance.
BACKGROUND: Many patients with extreme insulin resistance in combination with acanthosis nigricans are reported to have defective insulin receptor genes. Because acanthosis nigricans is commonly accompanied by severe hyperinsulinemia and obesity, and obesity is a major factor in insulin resistance, this study was initiated to assess the prevalence of mutations in the insulin receptor gene in Chinese patients with extreme insulin resistance defined by hyperinsulinemia, obesity and acanthosis nigricans. METHODS: Exons 1-22 of the insulin receptor gene were amplified by polymerase chain reaction (PCR) by from genomic DNA from 13 young subjects with clinical and metabolic features of extreme insulin resistance. They were also screened for nucleotide variation using single-strand conformation polymorphism (SSCP) combined with nucleotide sequence analysis. RESULTS: Variant SSCP patterns were detected in exons 1, 3, 6, 11, 12 and 17 of the insulin receptor gene. However, sequencing of amplified DNA fragments revealed that none of the variations were mutations. The SSCP variant in exon 1 was caused by a novel intron polymorphism (G-->T at position 13, 5' intron), while the SSCP variant in exon 12 was caused by a novel silent polymorphism Thr789 (ACG-->ACA). Variants in exons 3 and 17 corresponded to known silent polymorphisms: Gln276 (CAA-->CAG) and His1068 (CAC-->CAT), respectively. Another three variants in exons 3, 6 and 11 were also identified as known polymorphisms in the flanking introns. In addition, two alterations, a silent polymorphism Gly8 (GGA-->GGG) and a polymorphism in the 3' flanking intron (T-->G at position 74), were observed in exon 1 of the insulin receptor gene. CONCLUSIONS: Although the prevalence of insulin receptor gene mutations in this Chinese study population might be underestimated because of the sensitivity of SSCP, these results suggest that mutations at the insulin receptor locus are uncommon in subjects with features of hyperinsulinemia, obesity and acanthosis nigricans.
Adolescent↗
The sign of Leser-Trélat: a cutaneous sign of internal malignancy: weakened subepithelial matrix from the effect of neoplasms on the extracellular matrix of the host.
The sudden onset of many seborrheic keratoses (SK) associated with an internal malignancy (most commonly adenocarcinoma) is called the sign of Leser-Trélat. It is associated with acanthosis nigricans (AN) in 20% of the cases. There are marked changes in the extracellular matrix (ECM) around tumors. Various fractions and depolymerized glycosaminoglycans enter circulation. They can incorporate in the general extracellular matrix. Mechanical factors present in AN produce extrusions of this poor quality ECM in the form of papillae and folds. The poor quality of subepithelial extracellular matrix produces the marked epithelial changes of acanthosis nigricans which shows hyperkeratosis, papillomatosis, slight irregular acanthosis, and keratin material formation. The neoplasm can produce the same qualitative changes in the subepithelial ECM on otherwise normal appearing skin. When the altered same epithelial changes occur on this biologically altered skin the result is many SK (the sign of Leser-Trélat).
Acanthosis Nigricans↗