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PubMed1993

NTP technical report on the toxicity studies of a Chemical Mixture of 25 Groundwater Contaminants Administered in Drinking Water to F344/N Rats and B6C3F(1) Mice.

Toxicity studies were performed with a chemically defined mixture of 25 groundwater contaminants, using dose levels considered to have environmental relevance. The mixture contained 19 organic compounds and six metals (shown below); the selection of these compounds was based primarily on the frequency of their occurrence in United States Environmental Protection Agency surveys of groundwater contamination in the vicinity of hazardous waste disposal sites. This report focuses primarily on 26-week drinking water toxicity studies with male and female F344/N rats and B6C3F(1) mice. The endpoints evaluated included histopathology, clinical pathology, neurobehavioral studies, and reproductive toxicity. Additional studies using this same chemical mixture are briefly reviewed in this report and include an evaluation of spermatogenesis in B6C3F(1) mice exposed to the chemical mixture for 13 weeks, a continuous breeding study with Sprague-Dawley rats and CD-1(R) Swiss mice, studies of myelotoxicity in B6C3F(1) mice exposed to the chemical mixture for up to 31.5 weeks, studies of immunosuppression in B6C3F(1) mice exposed for up to 13 weeks, in vitro mutagenicity assays in Salmonella typhimurium and Escherichia coli, and measures of genetic damage in bone marrow and peripheral blood of F344/N rats and B6C3F(1) mice in 2-week drinking water studies. In a 26-week drinking water study in which rats were administered the chemical mixture at composite contaminant concentrations of 0, 11, 38, 113, or 378 ppm, no deaths occurred and the body weight gain of high-dose males was slightly less than that of the controls. Water consumption decreased with dose and was 24% to 28% less than that of the controls at the highest concentration. Changes in organ weights occurred primarily in high-dose rats and included increased absolute and relative liver and kidney weights in females, increased relative kidney weight in males, and decreased absolute and relative thymus weights in males and females. Hematologic assessments indicated that rats receiving 378 ppm developed a microcytic anemia consistent with that accompanying iron depletion. Multiple foci of inflammation occurred in the liver of exposed rats. In high-dose females, these liver lesions were especially prominent and included bile duct and oval cell hyperplasia. Inflammation also occurred in the mesenteric lymph nodes, the adrenal gland, and the spleen. The amount of hemosiderin in the spleens of rats receiving the higher concentrations of the chemical mixture was less than normal. Components of a chemical mixture of 25 groundwater contaminants include acetone, aroclor 1260, arsenic, benzene, cadmium, carbon tetrachloride, chlorobenzene, chloroform, chromium, 1,1-dichloroethane, 1,2-dichloroethane, 1,1-dichloroethylene, 1,2-trans-dichloroethylene, di(2-ethylhexyl) phthalate, ethylbenzene, lead, mercury, methylene chloride, nickel, phenol, tetrachloroethylene, toluene, 1,1,1-trichloroethane, trichloroethylene, xylenes. In a 26-week study in which mice were exposed to the chemical mixture at concentrations of 0, 11, 38, 113, and 378 ppm in drinking water, there were no clear adverse effects noted in survival, weight gain, clinical pathology parameters, or histopathologic evaluations. Water consumption decreased with increasing dose, and water consumption by high-dose mice was approximately 40% less than that by the controls. In neurobehavioral assessments, no clear treatment-related effects were observed in measures of forelimb and hindlimb grip strength, hindlimb footsplay, motor activity, response to a thermal stimulus, or startle response in rats or mice evaluated at 6-week intervals throughout the 26- week drinking water studies. There were no effects on sperm morphology or motility or on estrous cycle length in rats or mice receiving the chemical mixture during the 26-week studies. Sperm concentration was decreased in F(1) CD-1(R) Swiss mice during continuous breeding studies, although there were no clear adverse effects on the fertility of Sprague-Dawley rats or CD-1(R) Swiss mice in th CD-1® Swiss mice in these studies. Pup weight, the number of live males, and the number of male pups per litter were slightly decreased in dosed rats in the continuous breeding study in rats; the number of live female mouse pups in litters born of the F(0) and F(1) generations was decreased in the 378 ppm group. The significance of these observations, if any, is not known. F(1) mice receiving 378 ppm had increased incidences of hepatic inflammation compared to the controls. In female B6C3F(1) mice that received the chemical mixture in drinking water at concentrations as high as 756 ppm for 2 weeks or 378 ppm for 13 weeks, assessments of immune function showed suppression of hematopoietic stem cells and antigen-induced antibody-forming cells. This was manifested by impaired resistance to challenge with a nonlethal strain of mouse malaria, Plasmodium yoelii. Additional evidence of an adverse effect on hematopoietic stem cells was demonstrated by decreases in the in vitro colony-forming ability of granulocyte-macrophage progenitor cells and erythroid precursor cells isolated from female mice that had received the chemical mixture at a concentration of 378 or 756 ppm in 31.5 week studies. Potential genotoxic effects of the chemical mixture to the bone marrow of F344/N rats and B6C3F(1) mice were assessed in 2-week drinking water studies with concentrations as high as 756 ppm. Small increases in sister chromatid exchanges and micronucleated polychromatic erythrocytes occurred in the bone marrow of dosed male mice, and micronucleated polychromatic erythrocytes were also increased in dosed female mice. The chemical mixture did not induce mutations in Salmonella typhimurium strains TA98 and TA100 and did not induce DNA damage in Escherichia coli with or without metabolic activation. In summary, rats receiving drinking water containing a mixture of 25 common groundwater contaminants at levels of potential environmental relevance developed inflammatory lesions in the liver, spleen, lymph nodes, and adrenal gland, as well as evidence of an iron deficiency anemia. The inflammatory lesions could not be predicted based on the known toxic effects of the individual components of the chemical mixture. Mice exposed to similar concentrations of the chemical mixture did not show adverse effects in a standard toxicity study but developed deficits in bone marrow function, evidence of genetic damage, hepatic inflammation, and immunosuppression in other studies that generally included exposures to higher concentrations or exposures of longer duration. A no-observed-adverse-effect level for histologic injury (granulomatous inflammation of the liver) was 11 ppm in rats; however, no clear evidence for histologic injury was seen in mice exposed to concentrations of the chemical mixture as high as 378 ppm in a standard 26-week study. NOTE: These studies were supported in part by funds from the Comprehensive Environmental Response, Compensation, and Liability Act trust fund (Superfund) by an interagency agreement with the Agency for Toxic Substances and Disease Registry, U.S. Public Health Service.

Journal Article↗
PubMed1993

NTP technical report on the toxicity studies of Methylene Bis(thiocyanate) (CAS No. 6317-18-6) Administered by Gavage to F344/N Rats and B6C3F1 Mice.

Methylene bis(thiocyanate) is used as a biocide in a number of applications. Its major use is in water cooling systems and paper mills as an inhibitor of algae, fungi, and bacteria. Methylene bis(thiocyanate) was selected for study because of the potential for human exposure to the compound and because of the interest in organothiocyanates as a chemical class. Toxicity studies of methylene bis(thiocyanate) (approximately 98% pure) were conducted with male and female F344/N rats and B6C3F1 mice; the compound was administered to the animals by gavage in an aqueous methyl cellulose vehicle for 2 weeks or 13 weeks. In addition to these studies, the genetic toxicity of methylene bis(thiocyanate) was evaluated by determining mutagenicity in Salmonella typhimurium with and without S9 activation and frequency of micronucleated normochromatic erythrocytes in the peripheral blood of mice. In the 2-week studies, groups of five rats and five mice per sex were administered methylene bis(thiocyanate) at concentrations of 0, 10, 20, 40, 80, and 160 mg/kg body weight. All animals in the two highest dose groups (80 and 160 mg/kg) died by Day 2 of the studies. Except for one female rat, all animals receiving 40 mg/kg methylene bis(thiocyanate) also died before the end of the studies. Few significant gross lesions were observed in the 80 and 160 mg/kg groups. Clinical observations were similar to those reported for cyanide toxicity and included dyspnea, tremors. and ataxia. The stomach, which was identified as the target organ in rats and mice surviving for at least 24 hours, had necrotic inflammatory lesions of the mucosal surface of both the glandular and nonglandular portions. In the 13-week studies, groups of 10 rats and 10 mice per sex were administered methylene bis(thiocyanate) at concentrations of 0, 1, 2, 4, 8, and 16 mg/kg body weight. In the rat study, deaths occurred in the 2, 4, 8, and 16 mg/kg groups, while in the mouse study, deaths occurred only in the 8 and 16 mg/kg groups. As in the 2-week studies, the stomach was identified as the primary target organ. However, the lower doses administered in the 13-week studies resulted in gastric effects that were limited to the forestomach and consisted primarily of squamous mucosal hyperplasia and hyperkeratosis. Rats receiving the higher doses of methylene bis(thiocyanate) developed a mild anemia, and sperm motility was decreased in male rats receiving 4 or 8 mg/kg. Methylene bis(thiocyanate) was not mutagenic in S. typhimurium, with or without S9 activation. The frequencies of micronucleated normochromatic erythrocytes in the peripheral blood of dosed and control mice were similar. Chemical disposition studies of [14C]-labeled methylene bis(thiocyanate) were conducted in male F344 rats. In these studies, more than 90% of the administered radioactivity was eliminated in 48 hours. However, as the dose was increased from 0.2 to 1 to 10 mg/kg, greater percentages of the administered radioactivity remained in the tissues. Blood cyanide concentrations were increased shortly after the administration of 10 mg/kg [14C]-methylene bis(thiocyanate) but were similar to control values 2 hours after dosing. Overall, the toxic effects of methylene bis(thiocyanate) were consistent with those of an irritant chemical administered by gavage. There was also some indication that the release of cyanide may result in acute toxicity at the higher dose levels used in these studies. The no-observed-adverse-effect level for forestomach lesions in the 13-week studies was 4 mg/kg for male rats and 2 mg/kg for female rats and male and female mice. Synonyms: MBT; methylene-bis-thiocyanate; methylene bisthiocyanate; methylene dithiocyanate.

Journal Article↗
PubMed1995

NTP technical report on the toxicity studies of Isoprene (CAS No. 78-79-5) Administered by Inhalation to F344/N Rats and B6C3F1 Mice.

Isoprene, the 2-methyl analogue of 1,3-butadiene, has a high production volume and is used largely in the manufacture of synthetic rubber. Isoprene is also the major endogenous hydrocarbon exhaled in human breath. Two-week and 13-week inhalation toxicology studies were conducted in male and female F344/N rats and B6C3F1 mice to characterize potential adverse effects of isoprene. Male rats and male mice were also exposed to isoprene vapors for 6 months followed by a 6-month recovery period (stop- exposure protocol) to determine if isoprene produces a carcinogenic response similar to that of 1,3-butadiene after intermediate exposure durations. In addition to histopathology, evaluations included clinical pathology, tissue glutathione analyses, forelimb and hindlimb grip strength analyses, and sperm motility and vaginal cytology. Data from inhalation teratology studies of isoprene in rats and mice are also reported. In vitro genetic toxicity studies included assessments of mutagenicity in Salmonella typhimurium and sister chromatid exchanges and chromosomal aberrations in Chinese hamster ovary cells. In conjunction with the inhalation studies in mice, evaluations were also made of sister chromatid exchanges and chromosomal aberrations in bone marrow cells and micronuclei in peripheral blood of male mice exposed to isoprene for 12 days or 13 weeks. Target concentrations of isoprene in the inhalation chambers were 0, 438, 875, 1,750, 3,500, and 7,000 ppm in the 2-week studies; 0, 70, 220, 700, 2,200, and 7,000 ppm in the 13-week and stop-exposure studies; and 0, 280, 1,400, and 7,000 ppm in the teratology studies. In the 2-week studies, no changes related to chemical administration were observed in survival, body weight gain, clinical signs, hematologic or clinical chemistry parameters, or the incidence of gross or microscopic lesions in rats. In mice, there were no effects on survival; the mean body weight of males in the 7,000 ppm group was less than that of the controls. In mice, exposure to isoprene caused decreases in hematocrit values, hemoglobin concentrations, and erythrocyte counts, atrophy of the testis and thymus, cytoplasmic vacuolization of the liver, olfactory epithelial degeneration in the nasal cavity, and epithelial hyperplasia in the forestomach. Exposure to isoprene for 13 weeks produced no discernible toxicologic effects in rats. In the stop-exposure study, interstitial cell hyperplasia of the testis was observed in all male rats in the 7,000 ppm group after 6 months of exposure. Following the 6-month recovery period, male rats exposed to 700, 2,200, or 7,000 ppm isoprene had slightly greater incidences of interstitial cell adenomas of the testes than the controls. Exposure to isoprene for 13 weeks or 6 months produced no clear exposure-related effects on body weight gain in male or female mice; however, survival was decreased for male mice exposed to 7,000 ppm isoprene for 6 months. More notably, toxic and carcinogenic effects were induced at multiple organ sites in mice exposed to isoprene. After 6 months of exposure and 6 months of recovery, male mice exposed to 700 ppm or higher concentrations of isoprene had greater incidences of neoplasms of the liver (0 ppm, 7/30; 70 ppm, 3/30; 220 ppm, 7/29; 700 ppm, 15/30; 2,200 ppm, 18/30; 7,000 ppm, 17/28), lungs (2/30, 2/30, 1/29, 5/30, 10/30, 9/28), forestomach (0/30, 0/30, 0/30, 1/30, 4/30, 6/30), and harderian gland (2/30, 6/30, 4/30, 14/30, 13/30, 12/30) than the controls. In addition to the higher neoplasm incidences in male mice exposed to 700 ppm or greater, incidences of multiple neoplasms and/or neoplasms of greater malignancy were also higher than in the controls. Hematologic effects similar to those occurring in exposed mice in the 2-week study, plus greater mean cell volume values than in the controls, were observed after 24 days and after 13 weeks of exposure to isoprene. These hematologic effects, which were not accompanied by greater reticulocyte counts or a higher frequency of polychromatic erythrocytes than controls, were indicative of a nonresponsive, macrocytic anemia. In male mice in the stop-exposure study, partial hindlimb paralysis in the 7,000 ppm group and a dose-related decrease in grip strength were observed near the end of the 6-month exposure period. Other nonneoplastic effects in mice exposed to isoprene included spinal cord and sciatic nerve degeneration, skeletal muscle atrophy, degeneration of the olfactory epithelium, epithelial hyperplasia of the forestomach, increased estrous cycle length, testicular atrophy, and decreased epididymal weight, sperm head count, sperm concentration, and sperm motility. The inhalation teratology studies did not show maternal or developmental toxicity in Sprague-Dawley rats at exposures of up to 7,000 ppm isoprene; in CD-1® Swiss mice, exposure to isoprene resulted in lower fetal weights and a higher percentage of fetuses per litter with supernumerary ribs. Isoprene was not mutagenic in Salmonella typhimurium and did not induce sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells with or without exogenous metabolic activation; however, in mice, isoprene induced increases in the frequency of sister chromatid exchanges in bone marrow cells and in the frequency of micronucleated erythrocytes in peripheral blood. These inhalation studies showed that isoprene caused toxic effects in the testis of rats and at multiple organ sites in mice. In F344/N rats, exposure to 7,000 ppm isoprene for 6 months caused an increase in the incidence of testicular interstitial cell hyperplasia, and after 6 months of recovery there was a marginally increased incidence of benign testicular adenomas that may have been related to isoprene administration. No-observable-adverse-effect levels (NOAELs) for isoprene-induced toxic lesions in mice were: 70 ppm for nonresponsive, macrocytic anemia, decreased hindlimb grip strength, olfactory epithelial degeneration, and decreases in epididymal weights, spermatid head counts, sperm concentration, and sperm motility; 220 ppm for forestomach epithelial hyperplasia; 700 ppm for increased estrous cycle length; and 2,200 ppm for testicular atrophy, sciatic nerve degeneration, and muscle atrophy. A NOAEL was not achieved for spinal cord degeneration (less than 70 ppm) or developmental toxicity (less than 280 ppm, based on lower body weights of female fetuses). In addition, the 6-month inhalation exposure plus 6-month recovery (stop-exposure) study provided clear evidence of carcinogenicity of isoprene in the liver, lung, forestomach, and harderian gland of mice. Because these studies involved exposures of male rats and male mice to isoprene for only 6 months, they do not necessarily reveal the full carcinogenic potential of isoprene in these species. Most of the toxic and carcinogenic effects seen with isoprene were also caused by inhalation exposure to 1,3-butadiene. Synonyms: isopentadiene; 2-methyl-1,3-butadiene; beta-methylbivinyl.

Journal Article↗
PubMed1995

NTP technical report on the toxicity studies of Dibutyl Phthalate (CAS No. 84-74-2) Administered in Feed to F344/N Rats and B6C3F1 Mice.

Dibutyl phthalate is a phthalate ester with extensive use in industry in such products as plastic (PVC) piping, various varnishes and lacquers, safety glass, nail polishes, paper coatings, dental materials, pharmaceuticals, and plastic food wrap. Concomitant with this extensive worldwide use is the high potential for human exposure to dibutyl phthalate in the workplace and the home environment through direct sources as well as indirectly, through contamination of water, air, and foodstuffs. Because existing toxicity information was considered inadequate, the effects of exposure to dibutyl phthalate were examined in male and female F344/N rats and B6C3F1 mice in 13-week feed studies. Furthermore, due to concern over the potential for pervasive exposure of humans to dibutyl phthalate, additional perinatal studies examined rats and mice exposed as pups in utero, for the 4 weeks of lactation, and for an additional 4 weeks postweaning. Additional studies examined the effects on rats of combining perinatal and adult subchronic exposure. Due to the recognized biologic activity of this and other phthalates, hepatic peroxisome proliferation during the in utero and lactational phases and testicular toxicity during the perinatal period were also examined. Finally, reproductive assessment by continuous breeding (including crossover mating trials and offspring assessment) and genetic toxicity studies were also conducted. In the maximum perinatal exposure (MPE) determination study in rats, dibutyl phthalate was administered in the diet to dams during gestation and lactation, and to the pups postweaning for four additional weeks, at concentrations of 0, 1,250, 2,500, 5,000, 7,500, 10,000, and 20,000 ppm. Decreased weight gains were noted in dams exposed to 20,000 ppm during gestation and to dams exposed to 10,000 ppm during lactation. The gestation index (number of live pups per breeding female) was significantly lower in the 20,000 ppm group than in the controls, and pup mortality in this group was marked (100% by Day 1 of lactation); however, survival was 89% or greater in all other treatment groups. The mean body weight of pups in the 10,000 ppm group at Day 28 of lactation was approximately 90% of the mean weight of control pups. Pups were weaned onto diets containing dibutyl phthalate at the same concentrations fed to dams. After an additional 4 weeks of dietary administration, final mean body weights of pups in the 10,000 ppm groups were 92% of the control value for males and 95% of the control value for females. Hepatomegaly (increased relative liver weight) was observed in males in all exposed groups and in females receiving 2,500 ppm or greater. No gross lesions were observed at necropsy. Moderate hypospermia of the epididymis was diagnosed in all male rats in the 7,500 and 10,000 ppm groups; mild hypospermia of the epididymis was diagnosed in 2 of 10 males in the 5,000 ppm group. No degeneration of the germinal epithelium was detected in the testis of these rats. Thus, although toxicologically important, the epididymal hypospermia was not considered to be life threatening, and 10,000 ppm was recommended as the MPE concentration for male and female rats. In the subsequent subchronic toxicity study of dibutyl phthalate with perinatal exposure, dams were administered diets containing 0 or the MPE concentration (10,000 ppm) during gestation and lactation, and weaned pups were administered the same diets as their dams received for an additional 4 weeks, until the beginning of the 13-week exposure phase. Male and female rats then received diets containing dibutyl phthalate at concentrations of 0, 2,500, 5,000, 10,000, 20,000, and 40,000 ppm for 13 weeks. No mortality or toxicity was observed in dams during the perinatal phase of the study; however, before pups were culled at 4 days postpartum, the percentage of live pups per litter was 86% to 93% that of the controls. Through weaning, litter weights of exposed pups ranged from 89% to 92% of the control values. Ten control and ten exposed pups per sex were examined at the time of trol and ten exposed pups per sex were examined at the time of weaning; hepatomegaly and markedly increased peroxisomal enzyme activities (approximately 9-fold greater than the control values) were observed in exposed pups. Body weights of the perinatally exposed pups remained lower than those of the controls throughout the 4-week period before the 13-week adult exposures began. During the 13-week adult exposure phase, the final mean body weight of males in the MPE: 0 ppm control group (MPE rats, returned to the base diet for 13 weeks), was 95% that of the controls. The body weight gain of females in the MPE:0 ppm group was greater than that of the unexposed controls, and the final body weights of these two groups were similar. Body weight gains of rats treated with dibutyl phthalate as adults decreased with increasing exposure concentration; for rats that received the MPE concentration followed by 40,000 ppm for 13 weeks, final body weights were 51% of the control value for males and 74% of the control value for females. Hepatomegaly apparently regressed in rats in the MPE:0 ppm groups but was observed in male rats receiving 5,000 ppm or greater and in females receiving 2,500 ppm or greater. In males that received 20,000 ppm as adults, testis and epididymal weights were less than in the controls; males in the 40,000 ppm group also had a lower testis weight than the controls. Results of hematologic analyses conducted at the end of the 13-week exposure period suggested a mild anemia in male rats administered 10,000 ppm or greater as adults and female rats administered 40,000 ppm as adults. Hypocholesterolemia and hypotriglyceridemia were observed in male and female rats at the higher exposure concentrations. Hypotriglyceridemia was detected in females receiving 20,000 or 40,000 ppm and in males receiving 10,000 ppm or greater. Elevations in alkaline phosphatase activities and bile acid concentrations in male and female rats receiving 20,000 or 40,000 ppm as adults were indicative of cholestasis. Microscopic examination revealed hepatocellular cytoplasmic alteration, consistent with glycogen depletion, in male and female rats receiving a concentration of 10,000 ppm or greater. In the liver of rats receiving 40,000 ppm, small, fine, eosinophilic granules were also observed in the cytoplasm of hepatocytes. Ultrastructural examination suggested the presence of increased numbers of peroxisomes. Lipofuscin accumulation was detected in rats that received 10,000 ppm or greater. Consistent with the regression of the hepatomegaly in rats in the MPE:0 and MPE:2,500 ppm groups, peroxisomal enzyme activity was not elevated in these groups. Marked elevations of peroxisomal enzyme activity were detected, however, in males receiving 5,000 ppm or greater and in females receiving 10,000 ppm or greater; at the 40,000 ppm concentration, the highest concentration tested, enzyme activities were approximately 20 fold greater than the control values. Histopathologic examination of the testes revealed degeneration of the germinal epithelium, a mild to moderate focal lesion in rats in the 10,000 and 20,000 ppm groups and a marked, diffuse lesion in all males receiving 40,000 ppm; at 40,000 ppm, an almost complete loss of the germinal epithelium resulted. Testicular zinc concentrations were lower in the 40,000 ppm group than in the controls, a finding consistent with the marked loss of germinal epithelium at this exposure concentration. Spermatogenesis was evaluated in rats in the 0, 2,500, 10,000, and 20,000 ppm groups; rats administered 20,000 ppm had fewer spermatid heads per testis than the unexposed controls, and epididymal spermatozoal concentration was less than that in the MPE:0 ppm group. For comparison with the perinatal subchronic study, a standard 13-week evaluation of the toxicity of dibutyl phthalate in male and female rats was also conducted. In this study, rats received dibutyl phthalate at the same dietary concentrations used in the 13-week exposure phase of the study with perinatal exposure: 0, 2,500, 5,000, 10,000, 20,000, and 40,000 ppm. No deaths occurred in the standard study. Markedly reduced final mean body weights were observed in males and females in the 40,000 ppm groups (45% and 73% of control body weights, respectively); final mean body weights of males receiving 10,000 ppm or greater and females receiving 20,000 ppm or greater were lower than those of the controls. Hepatomegaly was observed in males that received 5,000 ppm or greater and in females that received 10,000 ppm or greater. Testis and epididymal weights of males in the 20,000 and 40,000 ppm groups were lower than those of the controls. A minimal anemia was detected in male rats receiving 5,000 ppm or greater. Hypocholesterolemia was observed in male and female rats receiving 20,000 or 40,000 ppm, and hypotriglyceridemia was detected in males in all exposed groups and in females receiving 10,000 ppm or greater. Elevations in alkaline phosphatase activity and bile acid concentration in male and female rats were considered indicative of cholestasis. Morphologic evaluation again confirmed the toxicity of dibutyl phthalate to the liver and testes of rats. Microscopic examination of the liver revealed hepatocellular cytoplasmic alterations, consistent with glycogen depletion, in male and female rats receiving 10,000 ppm or greater. In the liver of rats in the 40,000 ppm groups, small, fine, eosinophilic granules were also observed in the cytoplasm of hepatocytes. Ultrastructural examination suggested the presence of increased numbers of peroxisomes, and peroxisomal enzyme activity was elevated in the livers of male and female rats administered 5,000 ppm or greater; the enzyme activities in the 40,000 ppm groups were approximately 13-fold greater than the control value for males and 32-fold greater than the control value for females. Lipofuscin accumulation was detected in rats receiving 10,000 ppm or greater. Histopathologic examination of the testes revealed degeneration of the germinal epithelium, a mild to marked focal lesion in the 10,000 and 20,000 ppm groups and a marked, diffuse lesion in all males in the 40,000 ppm group; at 40,000 ppm, an almost complete loss of the germinal epithelium resulted. Testicular zinc concentrations were lower in the 20,000 and 40,000 ppm groups than in the controls. Serum testosterone values were also lower at these concentrations than in the controls. Spermatogenesis was evaluated in males in the 0, 2,500, 10,000, and 20,000 ppm groups; at 20,000 ppm, spermatid heads per testis and per gram testis, epididymal spermatozoal motility, and the number of epididymal spermatozoa per gram epididymis were lower than in the controls. All of these findings are consistent with the marked loss of germinal epithelium at these exposure concentrations. In the continuous breeding study, Sprague-Dawley rats received 0, 1,000, 5,000, or 10,000 ppm dibutyl phthalate in feed. Mean body weights of exposed dams at delivery and during lactation generally decreased with increasing exposure concentration. The mean pup weight at birth in the 10,000 ppm group was significantly lower than the control pup weight. The average number of live pups per litter in all exposed groups was lower than in the controls. Crossover mating trials in the F(0) generation revealed no effects on the fertility of male or female rats receiving 10,000 ppm. In contrast to the F(0) rats, mating, pregnancy, and fertility indices of F(1) rats were lower in the 10,000 ppm group than in the controls. Germinal epithelial degeneration of the testes and absence or under development of the epididymides were noted in F(1) males in the 10,000 ppm group. Interstitial cell hyperplasia was noted in 7 of 10 males in the 10,000 ppm group. These effects document the male and female reproductive toxicity of dibutyl phthalate in F(1) rats receiving 10,000 ppm and do not exclude the possibility of developmental toxicity to F2 offspring. In the MPE determination study in mice, dams received 0, 1,250, 2,500, 5,000, 7,500, 10,000, or 20,000 ppm dibutyl phthalate in feed during gestation and lactation; pups were weaned onto the same diets as the dams received and were exposed for an additional 4 weeks. The gestation period was longer in dams that received 2,500 ppm or greater than in the controls, and gestational body weight gain depressions were noted in dams receiving 7,500 ppm or greater. Only 5 of 20 females in the 10,000 ppm group delivered live pups, and none of the 20 females receiving 20,000 ppm delivered live pups. Only one pup in the 10,000 ppm group survived past Lactation Day 1; the number of live pups per litter in the 7,500 ppm group also remained low throughout lactation. No deaths of either male or female pups occurred after weaning. Initial (postweaning) and final body weights of male pups receiving 2,500 ppm or greater were significantly less than those of the control group. The mean body weights of exposed female pups were similar to the control body weight at weaning and remained similar throughout the 4 weeks postweaning. Hepatomegaly was present in male mice in all exposed groups, and the absolute liver weight of males administered 7,500 ppm was greater than that of the controls; although a similar change was apparent in females, no statistical differences between the liver weights of exposed and control females were detected. No treatment-related gross lesions were identified at necropsy, and no histopathologic lesions definitively associated with treatment were observed in male or female mice in the 7,500 ppm groups. The one surviving male pup in the 10,000 ppm group had cytoplasmic alteration in the liver, consistent with peroxisome proliferation. Developmental toxicity and fetal and pup mortality were suggested at concentrations as low as 7,500 ppm. No subchronic toxicity study with prior MPE exposure was conducted with mice, although an MPE concentration of 5,000 ppm was suggested by the data. In a standard 13-week toxicity study, mice received 0, 1,250, 2,500, 5,000, 10,000, or 20,000 ppm dibutyl phthalate in feed. No deaths occurred during this study. Mean body weights and weight gains of male and female mice decreased with increasing exposure concentration, and the decreases were significant for males and females that received 5,000 ppm or greater. Relative liver weights were greater in males and females receiving 5,000 ppm or greater than in the controls. A minimal anemia was suggested in female mice in the 20,000 ppm group. Although no gross lesions were observed at necropsy, microscopic examination revealed hepatocellular cytoplasmic alterations, consistent with glycogen depletion, in male mice receiving 10,000 or 20,000 ppm and female mice receiving 20,000 ppm. Small, fine, eosinophilic granules, consistent with peroxisome proliferation, were also observed in the cytoplasm of hepatocytes in males and females in the 20,000 ppm groups. Lipofuscin accumulation in the liver was detected in mice receiving 10,000 ppm or greater. In a continuous breeding study using Swiss (CD-1®) mice, animals received 0, 300, 3,000, or 10,000 ppm dibutyl phthalate in feed. The fertility index, average number of litters per breeding pair, and average number of live pups per litter in the 10,000 ppm group were lower than in the controls. Crossover mating trials of mice receiving 10,000 ppm revealed effects on dams in the F(0) generation, with a lower fertility index, number of live pups per litter, and pup weight than in the controls. Liver weights were greater in males and females, and the uterine weight was less in exposed dams than in the controls. No other changes were observed at necropsy or on histopathologic examination. These data document the female reproductive toxicity of dibutyl phthalate in F(0) mice. Dibutyl phthalate was not mutagenic in Salmonella typhimurium strain TA98, TA100, TA1535, or TA1537 with or without exogenous metabolic activation but did induce mutations in L5178Y mouse lymphoma cells treated without metabolic activation. In peripheral blood samples obtained from male and female mice at the end of the 13-week study, frequencies of micronucleated normochromatic erythrocytes were similar between exposed and control mice. Together, the studies in rodents suggest that young rodents (in utero and perinatal) respond in a manner qualitatively similar to that of adult rats and mice. Dibutyl phthalate induced toxic effects in rodents as pups in utero and during the lactational phases of development and also affected young adults, as evidenced by fetotoxicity and lethality, body weight gain decrements, increased liver weights, hepatic peroxisome proliferation, testicular toxicity, and female reproductive toxicity. Dibutyl phthalate was lethal to rat fetuses and rat and mouse neonates at dietary concentrations that were not toxic to dams. Otherwise, there was no teratogenic or morphologic evidence that rodent young were uniquely sensitive to the effects of short-term dibutyl phthalate treatment. Synonyms: 1,2-Benzenedicarboxylic acid dibutyl ester; benzene-o-dicarboxylic acid di-n-butyl ester; o-benzenedicarboxylic acid dibutyl ester; butyl phthalate; n-butyl phthalate; DBP; dibutyl 1,2-benzene dicarboxylate; dibutylphthalate; di-n-butylphthalate; di(n-butyl) phthalate; dibutyl-o-phthalate; phthalic acid dibutyl ester. Trade Names: Celluflex DBP; Elaol; Ergoplast FDB; Ersoplast FDA; Genoplast B; Hexaplas M/B; Palatinol C; Polycizer DBP; PX 104; RC Plasticizer DBP; Staflex DBP; Uniflex DBP; Unimoll DB; Witcizer 300; Witicizer 300. (NOTE: These studies were supported in part by funds from the Comprehensive Environmental Response, Compensation, and Liability Act trust fund (Superfund) by an interagency agreement with the Agency for Toxic Substances and Disease Registry, U.S. Public Health Service.)

Journal Article↗
PubMed1993

NTP technical report on the toxicity studies of Cupric Sulfate (CAS No. 7758-99-8) Administered in Drinking Water and Feed to F344/N Rats and B6C3F1 Mice.

Cupric sulfate is an inorganic salt which is widely used in industry, agriculture, and veterinary medicine. Its applications include use as an algicide in potable waters and as a feed additive and therapeutic agent in swine, sheep, and cattle. Because copper salts are found in human water supplies, toxicity studies of cupric sulfate pentahydrate were conducted in male and female F344/N rats and B6C3F1 mice by the drinking water (2-week studies only) and dosed feed routes (2-week and 13-week studies). Animals were evaluated for hematology, clinical chemistry, urinalysis, reproductive toxicity, tissue metal accumulation, and histopathology. In the 2-week drinking water studies, groups of five rats and five mice per sex received cupric sulfate at concentrations of 300 to 30,000 ppm for 15 days. One female rat, one male mouse, and three female mice in the 3000 ppm groups and all rats and mice in the 10,000 and 30,000 ppm groups died before the end of the studies. The remaining mice and rats in the 3000 ppm groups gained little or lost weight. Water consumption in the three highest dose groups of both species was reduced by more than 65%. Clinical signs observed in these groups were typical of those seen in moribund animals and were attributed to dehydration. The only gross or microscopic change specifically related to cupric sulfate toxicity was an increase in the size and number of cytoplasmic protein droplets in the epithelium of the renal proximal convoluted tubule in male rats from the 300 and 1000-ppm groups. In the 2-week feed studies, groups of five rats and five mice per sex were fed diets containing 1000 to 16,000 ppm cupric sulfate. No chemical-related deaths occurred in any dose group. Compared to the controls, rats and mice in the two highest dose groups had reduced body weight gains which were attributed to decreased feed consumption. Hyperplasia with hyperkeratosis of the squamous epithelium on the limiting ridge of the forestomach was seen in rats and mice of each sex; this lesion was more severe in rats than in mice. Inflammation of the liver, periportal to midzonal in distribution, occurred in rats in the 8000 and 16,000 ppm groups. Depletion of hematopoietic cells was evident in rats of each sex in the bone marrow (8000 and 16,000 ppm) and spleen (16,000 ppm). Kidneys of male and female rats in the 4000, 8000, and 16,000 ppm groups had an increased number and size of protein droplets in the epithelia of the renal cortical tubules. In the 13-week feed studies, groups of 10 rats per sex received diets containing 500 to 8000 ppm cupric sulfate, and groups of 10 mice per sex received diets containing 1000 to 16,000 ppm cupric sulfate for 92 days; estimates of cupric sulfate consumption ranged from 32 to 551 mg/kg per day for rats and 173 to 4157 mg/kg per day for mice. There were no chemical-related deaths in rats or mice, and no clinical signs of cupric sulfate toxicity were recorded. Final mean body weights were lower than those of the controls for animals of both species receiving doses of 4000 ppm cupric sulfate and greater. In mice in the 13-week studies, there was a dose-related decrease in liver weights. Hematologic, clinical chemistry, and urinalysis evaluations of rats in the 13-week study revealed variable chemical-related changes that were, for the most part, restricted to the 4000 and 8000 ppm groups. Increases in serum alanine aminotransferase and sorbitol dehydrogenase activities in both sexes were indicative of hepatocellular damage, as were increases in 5'-nucleotidase and bile salts in males. Decreases in mean cell volume, hematocrit, and hemoglobin indicated the development of a microcytic anemia, while increases in reticulocyte numbers at the same time points suggested a compensatory response to the anemia by the bone marrow. Increases in urinary glucose and N-acetyl-beta-D-glucosaminidase (a lysosomal enzyme) and aspartate aminotransferase (alpha-cytosolic enzyme) were suggestive of renal tubule epithelial damage. Dose-related increases in copper occurred in all male rat tissues examined (lissues examined (liver, kidney, plasma, and testis). These increases were accompanied by increases in zinc in the liver and kidney. Plasma calcium was significantly reduced in the 4000 and 8000 ppm groups, and there was a trend toward reductions in calcium in the kidney and testis as well. In the 8000 ppm group, plasma magnesium was significantly increased relative to the controls. Rats in the three highest dose groups had hyperplasia and hyperkeratosis of the forestomach, inflammation of the liver, and increases in the number and size of protein droplets in the epithelial cytoplasm and the lumina of the proximal convoluted tubules. These effects were similar to those seen in the 2-week feed study, and the incidence and severity of these lesions were dose related. Many of the droplets in male rat kidneys were large and had irregular crystalline shapes. These droplets stained strongly positive for protein but were negative by iron, PAS, and acid-fast (lipofuscin) staining methods. α-2-Microglobulin was present in the droplets of male rats, but there was no dose- related, qualitative difference in the content of this protein. In the 4000 and 8000 ppm groups, copper was distributed in a periportal to midzonal pattern in the liver and was restricted to the cytoplasm of the proximal convoluted tubule epithelium in the kidney. Copper was present in some, but not all, of the protein droplets. Transmission electron microscopy of the livers of rats of each sex revealed increases in the number of secondary lysosomes in hepatocytes in the periportal area. In mice of each sex receiving 4000 ppm cupric sulfate and higher in the 13-week study, there was a dose-related increase in hyperplasia with hyperkeratosis of the squamous mucosa on the limiting ridge of the forestomach. Minimal positive staining for copper was present in the liver and was limited to high-dose (16,000 ppm) male and female mice. Cupric sulfate produced no adverse effects on any of the reproductive parameters measured in rats or mice of either sex. In summary, administration of cupric sulfate to rats in feed or drinking water resulted in significant gastric changes and hepatic and renal damage. The primary lesion in rats was an increase in the size and number of proteinaceous droplets in the epithelial cytoplasm and lumen of the proximal convoluted tubule. For rats in the 13-week study, the no-observed-adverse-effect level (NOAEL) for evidence of histologic injury to the kidney was 1000 ppm for males and 500 ppm for females, while the NOAEL for liver inflammation was 1000 ppm for males and 2000 ppm for females. Hyperplasia with hyperkeratosis of the epithelium on the limiting ridge separating the forestomach from the glandular stomach was also seen in rats of each sex, and the NOAEL for this change was 1000-ppm cupric sulfate in the feed. Additionally, clinical pathology alterations noted in the 13-week study, along with histologic changes in bone marrow noted in the 2-week feed study, were indicative of a microcytic anemia with a compensatory bone marrow response. Mice appeared to be much more resistant to the toxic effects of cupric sulfate than rats. The primary target tissue in mice was the epithelium of the limiting ridge of the forestomach. The NOAEL for the hyperplasia and hyperkeratosis seen at this site in mice was 2000-ppm cupric sulfate in the feed. Synonyms: Chalcanthite; Copper sulfate; cupric sulfate pentahydrate; bluestone; blue vitriol; Roman vitriol; Salzburg vitriol. (NOTE: These studies were supported in part by funds from the Comprehensive Environmental Response, Compensation, and Liability Act trust fund (Superfund) by an interagency agreement with the Agency for Toxic Substances and Disease Registry, U.S. Public Health Service.)

Journal Article↗
PubMed2002

NTP Technical Report on the metabolism, toxicity and predicted carcinogenicity of diazoaminobenzene (CAS No. 136-35-6).

Diazoaminobenzene is used as an intermediate, complexing agent, and polymer additive. It is also an impurity in certain color additives used in cosmetics, food products, and pharmaceuticals. Diazoaminobenzene was selected for metabolism and toxicity studies based on the potential for worker exposure from its use in laboratories, positive Salmonella typhimurium gene mutation data, its presence as an impurity in foods and cosmetics, and the lack of adequate toxicity data. Several structural analogues and presumed metabolites of diazoaminobenzene are carcinogenic, providing evidence for the possible carcinogenicity of diazoaminobenzene. The chemical structure of diazoaminobenzene suggested that it would be metabolized into aniline and benzene; therefore, metabolism and disposition studies were performed in male and female F344/N rats and male B6C3F1 mice administered a single oral, dermal, or intravenous dose of diazoaminobenzene. Electron spin resonance (ESR) studies were conducted to assess the possible formation of a phenyl radical from the reduction of diazoaminobenzene by components of the cytochrome P450 mixed-function oxidase (P450) system in microsomes or by gut microflora in anaerobic cecal incubations. Bile duct-cannulated male F344/N rats were administered diazoaminobenzene and 5,5-dimethyl-1- pyrroline-N-oxide (DMPO) for in vivo determination of the DMPO-phenyl radical. 16-Day toxicity studies were performed to identify target organs of diazoaminobenzene following dermal application to male and female F344/N rats and B6C3F1 mice. In the disposition and metabolism studies, oral doses of 20 mg/kg to male and female rats and male mice were readily absorbed and excreted mainly in the urine, with exhalation of volatile organics accounting for about 1% of the dose. The only volatile metabolite detected in the breath was benzene, and all the metabolites in the urine were those previously shown to result from the metabolism of benzene and aniline in rats and mice. While dermal doses to rats and mice (2 and 20 mg/cm2) were only slightly absorbed, benzene and aniline metabolites were nonetheless detected in the urine. High circulating levels of benzene, aniline, and their metabolites were detected in the blood of rats administered 20 mg/kg diazoaminobenzene as early as 15 minutes after exposure. At 24 hours after dosing, diazoaminobenzene was detected at low levels (<1%) in the adipose tissue, blood, kidney, liver, muscle, skin, and spleen. Metabolites of benzene and aniline were also formed in an in vitro study using human liver slices. In the ESR spin-trapping experiments, the ESR spectrum of the DMPO-phenyl radical was detected when diazoaminobenzene was incubated with microsomes or P450 reductase, DMPO, and NADPH, or when incubated with cecal contents and DMPO. The DMPO-phenyl radical spectrum was not attenuated by the P450 inhibitor, 1-aminobenzotriazole, or carbon monoxide suggesting that P450s were not required. In in vivo experiments in which rats were administered diazoaminobenzene and DMPO, the DMPO-phenyl radical adduct was detected in bile within 1 hour after treatment. In the 16-day toxicity studies, groups of five male and five female F344/N rats and B6C3F1 mice received dermal applications of 0, 12.5, 25, 50, 100, or 200 mg diazoaminobenzene/kg body weight. Animals were evaluated for absolute and relative organ weights, for hematological effects, and for gross and microscopic lesions. No mortality occurred in rats. However, most male mice exposed to concentrations of 50 mg/kg or greater and female mice exposed to 200 mg/kg died. Body weights of male and female rats and female mice were less than those of the vehicle controls. Similar chemical-related toxicities were observed in both species. Clinical pathology data indicated a chemical-related methemoglobinemia and Heinz body formation in male and female rats and mice. Analysis of organ weights indicated possible chemical-related effects in the thymus, heart, spleen, kidney, and liver of rats and/or mice. Increases in the incidences of several skin lesionseral skin lesions, including hyperplasia of the epidermis and hair follicles, and inflammation in rats and mice and ulceration in female mice were observed. Other nonneoplastic lesions that were considered to be related to diazoaminobenzene administration were atrophy of the thymus, mandibular and/or mesenteric lymph nodes, and white pulp of the spleen, as well as splenic hematopoietic cell proliferation in rats and mice. In mice, there were increased incidences of atrial thrombosis, and necrosis was observed in the renal tubules and liver. Diazoaminobenzene was mutagenic in S. typhimurium strains TA98, TA100, and TA1537 with induced rat or hamster liver S9 enzymes; no activity was noted in strain TA1535, with or without S9. In vivo, two gavage administrations of either diazoaminobenzene or benzene induced highly significant increases in micronucleated polychromatic erythrocytes in bone marrow of male B6C3F1 mice at all doses tested. Diazoaminobenzene is metabolized to the known carcinogens benzene and aniline. Further evidence of this metabolism is that some toxic effects associated with aniline (methemoglobinemia) and benzene (atrophy of the lymphoid tissue) were identified. Based on these results, it is predicted that diazoaminobenzene is a carcinogen.

Animals↗
PubMed2003

Stiff guide technique: technical report and illustrative case.

Endovascular techniques are gaining wider acceptance in the treatment of intracranial lesions. Tortuous vasculature is a common reason for failure to treat an intracranial lesion, especially when balloon catheters or stents are used. In these cases, the guiding catheter often buckles into the aorta during an attempt to place the balloon or stent. In our experience, a stiff wire can be used to support the guiding catheter, allowing the balloon catheter or stent to more readily navigate tortuous vessels.

Angioplasty, Balloon↗
PubMed2002

NTP technical report on the toxicity studies of p-tert-butylcatechol (CAS No. 98-29-3) administered in feed to F344/N rats and B6C3F1 mice.

[molecular structure: see text] p-tert-Butylcatechol is used as an antioxidant, stabilizer, and polymerization inhibitor for styrene, butadiene, neoprene, and other olefins and reactive monomers. p-tert-Butylcatechol was nominated by the National Cancer Institute and the U.S. Food and Drug Administration for testing based on reports of its increasing levels of production and use and to compare the toxicity of p-tert-butylcatechol with that of similar antioxidants, butylated hydroxyanisole and butylated hydroxytoluene, which are added to food. Male and female F344/N rats and B6C3F1 mice were exposed to p-tert-butylcatechol (greater than 99% pure) in feed for 15 days or 14 weeks. Genetic toxicology studies were conducted in Salmonella typhimurium, rat bone marrow cells, and mouse peripheral blood erythrocytes. In the 15-day studies, groups of five male and five female rats and mice were fed diets containing 0, 3,125, 6,250, 12,500, 25,000, or 50,000 ppm p-tert-butylcatechol (equivalent to average daily doses of approximately 290 to 2,470 mg p-tert-butylcatechol/kg body weight to rats and 590 to 8,200 mg/kg to mice). All animals in the 50,000 ppm groups were killed moribund on day 8 (rats) or by day 7 (mice). Mean body weights of all groups of rats exposed to 6,250 ppm or greater were significantly less than those of the controls. Mean body weights of male mice exposed to 12,500 or 25,000 ppm and of 25,000 ppm female mice were significantly less than those of the controls. Female rats, male and female mice in the 25,000 ppm groups, and 12,500 ppm male mice lost weight during the studies. Feed consumption by exposed rats generally decreased with increasing exposure concentration; feed consumption by exposed mice was similar to that by the controls. Thymus weights of 25,000 ppm rats and mice were significantly less than those of the controls. Gross findings noted at necropsy included thin carcasses for three male and all female rats in the 12,500 ppm groups and all male and female rats and mice in the 25,000 and 50,000 ppm groups. No exposure-related lesions were observed microscopically. In the 14-week studies, groups of 10 male and 10 female rats and mice were fed diets containing 0, 781, 1,562, 3,125, 6,250, or 12,500 ppm p-tert-butylcatechol (equivalent to average daily doses of approximately 70 to 1,030 mg/kg to rats and 135 to 2,815 mg/kg to mice). All animals survived to the end of the studies. Mean body weights of male rats exposed to 1,562 ppm or greater, female rats exposed to 3,125 ppm or greater, male mice exposed to 12,500 ppm, and female mice exposed to 6,250 or 12,500 ppm were significantly less than those of the controls. Feed consumption by male and female rats in the 6,250 and 12,500 ppm groups at week 1 and the 12,500 ppm groups at week 14 was less than that by the controls; feed consumption by exposed and control mice was similar. An erythrocytosis, indicated by increased hematocrit values, hemoglobin concentrations, and erythrocyte counts, was observed in 6,250 and 12,500 ppm rats on day 4 and in 12,500 ppm rats on day 22. At these time points, a transient hepatic effect was demonstrated by increases in alanine aminotransferase activities and bile salt concentrations in exposed rats. In 12,500 ppm male rats, absolute left cauda epididymis, epididymis, and testis weights were decreased by 15%, 10%, and 9%, respectively, compared to the controls. The number of spermatid heads per testis and epididymal sperm motility of male rats in the 12,500 ppm group were significantly less than those of the controls. The numbers of cycling female rats and females with regular estrous cycles were decreased in the 6,250 and 12,500 ppm groups. Exposed groups of females had significantly fewer estrous cycles than did the controls. Estrous cycle length increased with increasing exposure concentration; female rats in the 6,250 and 12,500 ppm groups had significantly longer cycles and spent more time in diestrus and less time in proestrus, estrus, and metestrus than did the controls. Female mice in the 12,500 ppm group had a significantly longer estrous cycle than did the controls. The incidences of hyperkeratosis of the forestomach epithelium were significantly increased in male and female rats in all exposed groups and in 12,500 ppm female mice. The incidences of hyperplasia of the forestomach epithelium were significantly increased in male and female rats exposed to 3,125 ppm or greater, male mice exposed to 12,500 ppm, and female mice exposed to 6,250 or 12,500 ppm. The severities of the forestomach lesions were minimal to moderate in male rats and minimal to mild in female rats and in mice. All male rats exposed to 6,250 or 12,500 ppm had minimal cytoplasmic alteration in the liver. The absorption, distribution, metabolism, and excretion of p-tert-butylcatechol following intravenous injection, gavage dosing, or dermal application were determined in male F344/N rats and B6C3F1 mice. The absorption of [(14)C]-p-tert-butylcatechol following gavage dosing or dermal application was high. The percent absorption following dermal application increased with increasing dose. Peak concentrations of [(14)C]-p-tert-butylcatechol equivalents in plasma were reached 1 hour after gavage dosing (200 mg/kg) and 2 hours after dermal application (60 mg/kg); no parent compound was detected in the plasma extracts. Regardless of route of administration, p-tert-butylcatechol derived radioactivity was readily excreted in the urine and was markedly nonpersistent in the tissues. p-tert- Butylcatechol was excreted as p-tert-butylcatechol sulfate and other polar metabolites that included predominately sulfate conjugates; it was not excreted as the parent compound. One metabolite was determined to be an O-methyl- ON-sulfate of p-tert-butylcatechol. p-tert-Butylcatechol (10 to 1,000 microg/plate) was not mutagenic in any of several strains of S. typhimurium with or without rat or hamster liver S9. Bone marrow micronucleus tests in which 125 to 500 mg/kg p-tert-butylcatechol was administered three times by intraperitoneal injection to male rats gave negative results. No increases in the frequencies of micronucleated normochromatic erythrocytes were observed in the peripheral blood of male or female mice administered p-tert-butylcatechol in feed for 14 weeks. No significant alteration in the percentage of polychromatic erythrocytes in mouse bone marrow was observed. In summary, the primary toxicity of p-tert-butylcatechol was to the forestomach of rats and mice. In the 14-week study in rats, forestomach toxicity was observed at all exposure concentrations, and the no-observed-adverse-effect level (NOAEL) was not reached for this effect. In the 14-week study in mice, the NOAEL for forestomach toxicity was 1,562 ppm.

Administration, Cutaneous↗
PubMed1992

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↗