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PubMed1997

NTP technical report on toxicity studies of t-butyl alcohol (CAS No. 75-65-0). Administered by inhalation to F344/N rats and B6C3F1 mice.

t-Butyl alcohol is widely used in the manufacture of perfumes and a variety of cosmetics. It is also used as a raw material in the production of isobutylene, which may be used to produce methyl tertiary butyl ether, a common gasoline additive, or to produce butyl elastomers used in the production of automobile tires. The National Cancer Institute nominated t-butyl alcohol to the NTP for study as a result of a review of chemicals found in drinking water. In addition to the high annual production and the potential for occupational exposure, there is also a potential for human exposure to t-butyl alcohol by the inhalation route from its use as an additive in unleaded gasoline. Therefore, toxicity studies of t-butyl alcohol were conducted in male and female F344/N rats and B6C3F1 mice by whole-body inhalation. Animals were evaluated for hematology, clinical chemistry, urinalysis, reproductive toxicity, and histopathology. The genetic toxicity of t-butyl alcohol was assessed by testing the ability of the chemical to induce mutations in various strains of Salmonella typhimurium and L5178Y mouse lymphoma cells or sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells, and by measuring the frequency of micronucleated erythrocytes in rat bone marrow and mouse peripheral blood. In the 18-day inhalation studies, groups of five male and five female rats and mice were exposed to t-butyl alcohol by inhalation at concentrations of 450, 900, 1,750, 3,500, and 7, 000 ppm for 6 hours per day, 5 days per week, for 12 exposure days. All rats and mice exposed to 7,000 ppm were killed moribund following a single 6-hour exposure. One 3,500 ppm male mouse died on day 3. Final mean body weights of 3,500 ppm male and female rats were significantly lower than those of the controls. Final mean body weights and body weight gains of all other exposed groups were similar to those of the controls. In animals exposed to 3.500 ppm, the thymus weights of male and female rats and female mice were less than those of the controls. The liver weights of male and female mice exposed to 3,500 ppm were greater than those of the controls. No grss or microscopic lesion were present in rats or mice. In the 13-week inhalation studies, groups of 10 male and 10 female rats and mice were exposed to t-butyl alcohol at concentrations of 0, 135, 270, 540, 1,080, and 2,100 ppm for 6 hours per day, 5 days per week, for 13 weeks. One 2,100 ppm and five 1,080 ppm male mice died before the end of the studies. The final mean body weight of 2,100 ppm female mice and the mean body weight gains of 1,080 and 2,100 ppm female mice were significantly lower than those of the controls. Clinical findings of toxicity in the 1,080 ppm male mice died during the studies included rough coats and emaciated appearance, hypoactivity, and prostration. Minimal decreases in hematocrit values, hemoglobin concentrations, and erythrocyte counts occurred in the 1,080 and 2,100 ppm male rats at week 13. Hemoglobin concentrations and/or hematocrit values were also minimally decreased in male rats in the lower exposure groups. At week 13, a minimal decrease in urine pH occurred in the 1,080 ppm female and 2,100 ppm male and female rats. Neutrophilia occurred in the 2,100 ppm male mice. Organ weight differences in exposed rats included increased absolute and relative kidney weights of 1,080 ppm males and 2,100 ppm males and females and increased relative liver weights of 1,080 and 2,100 ppm females. There were no treatment-related gross findings in male or female rats or mice; no microscopic lesion occurred in female rats or male or female mice that survived to the end of the study. In male rats, there was an exposure concentration-related increase in the severity of chronic nephropathy. Splenic lymphoid depletion was present in male mice that died during the studies; this lesion was presumed to be secondary to stress. t-butyl alcohol produced no adverse effects on reproductive parameters in male or female rats or mice. The results of all tests of t-butyl alcohol for induction of genetic damage in vitro and in vivo were negative. In vitro, t-butyl alcohol was negative in Salmonella typhimurium and mouse lymphoma cell mutation test, and it did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells. These in vitro studies were conducted with and without metabolic activation (S9). In vivo, no increase in the frequency of micronucleated erythrocytes was observed in peripheral blood samples from mice administered t-butyl alcohol in drinking water for 13 weeks. Also, induction or micronucleated erythrocytes was noted in bone marrow cells of rats administered t-butyl alcohol by intraperitoneal injection. In summary, inhalation exposure of rats and mice to t-butyl alcohol resulted in deaths following a single 7,000 ppm exposure and clinical findings of alcohol toxicity (hyper- and hypoactivity, ataxia) at concentrations of 900 ppm and greater in rats and 1,750 ppm and greater in mice. In 13-week studies at concentrations up to 2,100 ppm, only one death (that of a 2,100 ppm mouse) was attributed to chemical exposure. The most notable evidence of toxicity at the end of 13 weeks was limited to males and consisted of increased kidney weights, which correlated microscopically to increased severity of chronic nephropathy. Reproductive parameters in male and female rats and mice were unaffected after 13 weeks of exposure, and the results of all tests for genetic toxicity were negative.

Administration, Inhalation↗
PubMed1996

NTP technical report on toxicity studies of urethane in drinking water and urethane in 5% ethanol administered to F344/N rats and B6C3F1 mice.

Urethane, a byproduct of fermentation found in alcoholic beverages, is carcinogenic in rodents and is classified by the International Agency for Research on Cancer as a possible human carcinogen. The United States Food and Drug Administration nominated urethane for study because of the widespread exposure of humans through the consumption of fermented foods and beverages and because of a lack of adequate dose-response data about the carcinogenicity of urethane with and without the coadministration of ethanol. Comparative studies of urethane in drinking water and in 5% ethanol were conducted to investigate possible effects of ethanol on urethane toxicity. Toxicokinetic studies of urethane in drinking water and in 5% ethanol and genetic toxicity studies of urethane in vivo and in vitro were also conducted. Groups of 10 male and 10 female F344/N rats and B6C3F1 mice, 6 weeks of age, received 0, 110, 330, 1,100, 3,300, or 10,000 ppm urethane in drinking water or in 5% ethanol for 13 weeks. Toxicokinetic evaluations were performed for urethane in the plasma of male mice after 13 weeks of administration in drinking water or 5% ethanol. The mutagenicity of urethane in Salmonella typhimurium strains TA97, TA98, TA100, TA1535, and TA1537 with and without S9 was tested at doses up to 16,666 micrograms/plate; urethane was also tested for induction of sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells and sex-linked recessive lethal mutations and chromosomal reciprocal translocations in Drosophila melanogaster. The frequency of micronucleated erythrocytes induced in peripheral blood and bone marrow cells of mice by urethane in drinking water and in 5% ethanol was also evaluated. In rats that received urethane in drinking water, seven males and four females administered 10,000 ppm and one female administered 3,300 ppm died before the end of the study; body weight gains were reduced at these concentrations. Two males and all females given 10,000 ppm urethane in 5% ethanol died during the study, and the body weight gains of males and females that received 3,300 ppm were lower than those of the controls. Relative right kidney, liver, and lung weights of males and females and relative right testis weights of males administered 1,100 ppm or greater were generally higher than those of the controls in each study. Leukopenia and lymphopenia were observed in rats receiving urethane in either drinking water or ethanol and occurred in males receiving 330 ppm or greater and females receiving 110 ppm or greater. Other differences in hematology and clinical chemistry variables were not considered to be biologically significant. Lymphoid depletion of the spleen, lymph nodes, and thymus was observed in male and female rats receiving 1,100, 3,300, or 10,000 ppm urethane in drinking water. Cellular depletion of the bone marrow occurred in males and females in the 10,000 ppm groups. Hepatocellular fatty changes and clear cell foci of alteration were noted in the liver of males and females that received 3,300 or 10,000 ppm. The incidences of nephropathy were significantly increased in female rats that received 1,100 ppm or greater; the severity of this lesion in exposed males and females was greater than that in the controls. Females that received 330 ppm or greater had higher incidences of cardiomyopathy than the controls; the severity of this lesion was greater in males in the 10,000 ppm group and females in the 3,300 and 10,000 ppm groups than in the controls. In rats that received urethane in 5% ethanol, lymphoid depletion occurred in males and females in the 3,300 and 10,000 ppm groups. Cellular depletion of the bone marrow was observed in males and females in the 10,000 ppm groups. Only males in the 10,000 ppm group had hepatocellular fatty change (8/10) and clear cell foci (1/10); the incidence and severity of nephropathy in males and females and cardiomyopathy in males were similar to those in rats administered urethane in drinking water; however, no cardiomyopathy was observed in females receiving urethane in ethanol. The estrous cycle length of females receiving urethane in ethanol appeared to be longer than that of females receiving urethane in drinking water. Because cycle length was longer in the 10,000 ppm groups than in the controls in both the drinking water and ethanol vehicle studies, this difference may represent an exacerbation of the toxicity of urethane. A longer estrous cycle may be a sign of reproductive impairment and correlates with a decrease in female fecundity. All mice administered 10,000 ppm urethane in either vehicle died. All mice that received 3,300 ppm urethane in drinking water died, while only one male and four females receiving 3,300 ppm urethane in 5% ethanol died. Body weight gains of males and females in all 1,100 ppm groups were less than those of the respective controls, but the weight gains of mice receiving 1,100 ppm urethane in 5% ethanol were greater than those of mice receiving urethane in drinking water. The mean body weights of the lower exposure groups were similar to those of the respective controls, and there were no other differences between the body weights of mice receiving urethane in drinking water and those receiving urethane in 5% ethanol. Fluid consumption, and therefore total urethane intake, appeared lower in mice receiving the 5% ethanol vehicle than in those receiving the water vehicle. The relative right kidney, liver, and lung weights of males and females administered urethane in drinking water or ethanol were generally greater than those of the controls. Clearance of urethane from the plasma of male mice was complete within 2 hours after urethane was administered in water, but urethane was not cleared 12 hours after administration in 5% ethanol. At the end of 13 weeks of urethane administration, the plasma urethane elimination half-life was 0.8 hours; the kinetics were similar for concentrations of 110, 330, and 1,100 ppm urethane in water and in ethanol. However, at each exposure level, the plasma urethane concentration was four times greater for urethane administered in 5% ethanol than for urethane administered in drinking water, indicating a possible inhibition of urethane metabolism by ethanol. Kinetic measurements for elimination by female mice could not be obtained from the data collected. In mice administered urethane in drinking water, lung inflammation occurred in males and females that received 1,100 ppm or greater. Alveolar epithelial hyperplasia occurred in the lungs of males in the 330 and 1,100 ppm groups and females in the 1,100 ppm group; one male mouse in the 330 ppm group had an alveolar/bronchiolar adenoma (see the following summary table). Mice receiving urethane in 5% ethanol had lower incidences and severity of lung inflammation but generally greater incidences and severity of alveolar epithelial hyperplasia than mice receiving the same concentrations of urethane in drinking water. Alveolar/bronchiolar adenomas occurred in four males and one female administered urethane in ethanol. [table: see text] Nephropathy was observed in males and females that received urethane in either vehicle, and the lesions in female mice were more severe than those in male mice; ethanol did not appear to increase the incidence or severity of nephropathy. Cardiomyopathy occurred in males and females that received 1,100 or 3,300 ppm urethane in drinking water and in females that received 3,300 ppm urethane in ethanol. Lymphoid depletion occurred in mice that received 3,300 or 10,000 ppm urethane; 5% ethanol did not appear to enhance these effects. However, urethane in 5% ethanol induced ovarian atrophy; the incidence of this lesion was lower in females receiving urethane in drinking water. A concentration of 1,100 ppm urethane in either drinking water or ethanol effectively stopped estrous cycling. Urethane is clearly genotoxic in vitro and in vivo. In vitro, urethane induced mutations in Salmonella typhimurium strain TA1535 in the presence of liver S9 enzymes. Sister chromatid exchanges were induced in cultured Chinese hamster ovary (CHO) cells with and without S9. However, no induction of chromosomal aberrations was observed in CHO cells treated with urethane, with or without S9. In vivo, urethane induced sex-linked recessive lethal mutations and reciprocal translocations in germ cells of adult male Drosophila melanogaster fed urethane. Significantly increased frequencies of micronucleated erythrocytes were observed in peripheral blood obtained from male and female mice after 45 days of exposure and in bone marrow and peripheral blood obtained after 13 weeks of exposure to urethane in drinking water. There appeared to be no significant difference in the magnitude of the response in the peripheral blood micronucleus test between mice administered urethane in drinking water and mice administered urethane in 5% ethanol. In summary, concentrations of 1,100 ppm urethane or greater in drinking water caused lymphoid and bone marrow cell depletion and hepatocellular lesions and increased the severity of nephropathy and cardiomyopathy in male and female rats. The lethal effects of 10,000 ppm urethane were slightly exacerbated by 5% ethanol in female rats. Urethane administered in drinking water induced lung inflammation, alveolar and bronchiolar hyperplasia, alveolar/bronchiolar adenomas, nephropathy, cardiomyopathy, lymphoid and bone marrow cell depletion, seminiferous tubule degeneration, and ovarian atrophy and follicular degeneration in mice. In female mice, 5% ethanol appeared to exacerbate ovarian atrophy. Mice administered urethane in 5% ethanol consumed less fluid, and therefore less urethane, than mice receiving urethane in drinking water. Coadministration of urethane and ethanol inhibited the clearance of urethane from plasma. (ABSTRACT TRUNCATED)

Animals↗
PubMed2000

NTP technical report on the toxicity studies of methacrylonitrile (CAS No. 126-98-7). Administered by gavage to F344/N rats and B6C3F1 mice.

Methacrylonitrile is an aliphatic nitrile used extensively in the preparation of homo- and copolymers, elastomers, and plastics and as a chemical intermediate in the preparation of acids, amides, esters, and other nitriles. This aliphatic nitrile is also used as a replacement for acrylonitrile in the manufacture of an acrylonitrile/butadiene/styrene-like polymer. Methacrylonitrile was nominated for toxicity and carcinogenicity testing by the National Cancer Institute due to its high production volume and extensive use, the lack of chronic or carcinogenicity data, and its structural resemblance to the known rat carcinogen acrylonitrile. The current 13-week studies were conducted as part of an overall effort by the NTP to assess the toxicity and carcinogenicity of methacrylonitrile. During the 13-week studies, groups of 20 male and 20 female F344/N rats were administered 0, 7.5, 15, 30, 60, or 120 mg methacrylonitrile/kg body weight in deionized, purified water by gavage. Groups of 20 male and 20 female B6C3F1 mice were administered 0, 0.75, 1.5, 3, 6, or 12 mg/kg methacrylonitrile. Ten male and ten female rats and mice from each group were evaluated on day 32. The results of these studies clearly revealed that male rats are more sensitive than females to methacrylonitrile treatment. In the rat study, 19 males and one female administered 120 mg/kg and two males administered 60 mg/kg died during the first week of the study. Males in the 60 mg/kg group at the 32-day interim evaluation and at 13 weeks and females in the 120 mg/kg group at 13 weeks had significantly lower final mean body weights and body weight gains than did the vehicle controls; the surviving male in the 120 mg/kg group also weighed less than the controls at the 32-day interim evaluation. Clinical findings of toxicity were dose dependent and included lethargy, lacrimation, tremors, convulsions, ataxia, and abnormal breathing. There was hematologic evidence indicating that administration of methacrylonitrile induced minimal, normocytic, normochromic anemia. At the 32-day interim evaluation, a minimal dose-related anemia was evidenced by decreases in hematocrit values, hemoglobin concentrations, and erythrocyte counts in male and female rats. The anemia ameliorated by week 13. Administration of methacrylonitrile resulted in dose-related increases in serum thiocyanate and blood cyanide concentrations of male and female rats. These changes were expected and would be consistent with the in vivo metabolism of methacrylonitrile to cyanide. Blood cyanide concentrations were generally higher in males than in females, which may explain the higher sensitivity of males to the lethal effect of methacrylonitrile. There was also biochemical evidence of increased hepatocellular leakage and/or altered function in dosed male rats, suggesting that the liver may be a target organ for toxic effects of methacrylonitrile. Minimal, but significant, decreases in absolute right kidney and thymus weights (32-day interim evaluation) and increases in liver and stomach weights (week 13) occurred in male rats that received 60 mg/kg compared to the vehicle controls. In female rats, stomach weights of the 60 and 120 mg/kg groups were significantly greater and thymus weights of the 120 mg/kg group were significantly less than those of the controls on day 32 and at week 13; liver weights were also significantly greater in females in the 120 mg/kg group than in the vehicle controls on day 32. Male and female rats administered 60 mg/kg and females administered 120 mg/kg had significantly greater incidences of metaplasia of the nasal olfactory epithelium on day 32 and at the end of the study than did the vehicle controls; incidences of olfactory epithelial necrosis were also significantly greater in females in the 60 and 120 mg/kg groups than in the vehicle controls on day 32. Incidence and/or severity increased with increasing dose in females; however, the mortality in male rats administered 120 mg/kg made it difficult to assess the dose-response relationship in males. The no-observed-adverse-effect level for the nasal cavity of rats was 30 mg/kg. Female rats administered 60 or 120 mg/kg methacrylonitrile had significantly longer estrous cycles than did the vehicle controls. Females in the 60 mg/kg group spent more time in diestrus than the vehicle controls. One male and one female mouse in the 12 mg/kg groups died early. Methacrylonitrile administration caused no significant differences in final mean body weights or body weight gains. Clinical findings included lethargy, tremors, ataxia, convulsions, and abnormal breathing. At the 32-day interim evaluation, stomach weights of males administered 3 mg/kg or greater were significantly greater and thymus weights of males in the 12 mg/kg group were significantly less than those of the vehicle controls. At week 13, however, the stomach weights of only males in the 12 mg/kg group were increased relative to the vehicle controls. No treatment-related histopathologic lesions occurred in mice. Methacrylonitrile did not induce mutations in any of several strains of Salmonella typhimurium, with or without S9 activation, and did not induce sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster fed methacrylonitrile during the larval stage. Results of in vivo bone marrow micronucleus tests with methacrylonitrile in male rats and mice were also negative. In summary, gavage administration of methacrylonitrile to rats and mice resulted in dose-dependent lethargy, tremors, lacrimation, convulsions, and abnormal breathing. However, these effects were more pronounced in rats than mice; these differences may be attributed to the higher doses of methacrylonitrile administered to rats. Body weight gain and survival data of rats demonstrated that males are more sensitive to methacrylonitrile dosing than females. There is an apparent correlation between blood cyanide concentrations and survival rates, with males having greater cyanide concentrations and lower survival rates than female rats administered methacrylonitrile. Microscopically, the only target of methacrylonitrile toxicity was the olfactory epithelium of the nasal cavity. Necrotic and metaplastic effects were induced in male and female rats that received 60 or 120 mg/kg per day. No similar lesions were observed in mice administered methacrylonitrile. The no-observed-adverse-effect level for olfactory epithelial lesions in male and female rats administered methacrylonitrile for 13 weeks was 30 mg/kg per day. No clear chemical-related effects were observed in male or female mice administered methacrylonitrile for 13 weeks by gavage at doses up to 12 mg/kg per day.

Animals↗
PubMed2000

NTP Technical Report on the Toxicity Studies of 1,1,1-Trichloroethane (CAS No. 71-55-6) Administered in Microcapsules in Feed to F344/N Rats and B6C3F1 Mice.

1,1,1-Trichloroethane is a widely used solvent in industry and in household products such as cleaning agents, wallpaper and carpet glues, carpets, spray and solid insecticides, and rodenticides. 1,1,1-Trichloroethane was studied because of its widespread use in industry and in the home and the potential for human exposure. Groups of 10 male and 10 female F344/N rats and B6C3F1 mice were given 5,000, 10,000, 20,000, 40,000, or 80,000 ppm microencapsulated 1,1,1,-trichloroethane in feed for 13 weeks. Groups of 10 male and 10 female rats and mice served as untreated controls and received feed without microcapsules; additional groups of 10 male and 10 female rats and mice served as vehicle controls and received feed with empty microcapsules. Animals were evaluated for clinical pathology (rats only), reproductive system effects, and histopathology. Genetic toxicity studies were conducted in Salmonella typhimurium, L5178Y mouse lymphoma cells, and cultured Chinese hamster ovary cells. In addition, peripheral blood slides from the mice in the 13-week study were analyzed for frequency of micronucleated erythrocytes. All rats survived to the end of the study. The final mean body weights of exposed rats were within 10% of those of the untreated and vehicle controls. Feed consumption by exposed groups of male and female rats was similar to that by the control groups, suggesting that the diet was palatable to the animals. Based on average feed consumption values, male rats ingested approximately 300, 600, 1,200, 2,400, or 4,800 mg 1,1,1-trichloroethane/kg body weight per day, and females received 300, 650, 1,250, 2,500, or 5,000 mg/kg per day. In general, changes in clinical pathology parameters were minor, sporadic, and inconsistent between males and females; these differences were not considered to be treatment related or biologically significant. The liver weights of female rats administered 80,000 ppm were significantly less than those of the untreated and vehicle controls. Male rats exposed to 10,000 ppm or greater had a spectrum of nonneoplastic kidney lesions consistent with hyaline droplet nephropathy. No treatment-related gross or microscopic lesions were observed in female rats. There were no exposure-related deaths in mice. Based on average feed consumption values, male mice ingested approximately 850, 1,770, 3,500, 7,370, or 15,000 mg/kg per day, and female mice received 1,340, 2,820, 5,600, 11,125, or 23,000 mg/kg per day. Even though feed consumption by exposed groups was slightly greater than that by the controls, the mean body weights of male and female mice administered 20,000 ppm or greater were significantly less than those of the untreated and vehicle controls. The heart, kidney, and lung weights of the vehicle control male mice were significantly greater than those of the untreated controls. There were no biologically significant differences in organ weights between exposed and control mice. No gross or microscopic lesions in male or female mice were attributed to chemical exposure. Epididymal spermatozoal concentrations of male rats and mice given 80,000 ppm were significantly less than those of the vehicle controls. 1,1,1-Trichloroethane was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537, with or without S9 metabolic activation. In the mouse lymphoma assay for induction of trifluorothymidine resistance in L5178Y cells, 1,1,1-trichloroethane gave a negative response in one test (with and without S9) and an equivocal response in a second test (in the presence of S9). Results of a sister chromatid exchange test in cultured Chinese hamster ovary cells were considered to be equivocal due to an unrepeated questionable response obtained in the presence of S9 in a single trial; without S9, results were negative. 1,1,1-Trichloroethane induced chromosomal aberrations in cultured Chinese hamster ovary cells in the absence of S9; with S9, the increase in aberrations noted in a single trial was not significant. A small increase in the frequency of micronucleated normochromatic erythrocytes was noted in peripheral blood slides from male mice administered 1,1,1-trichloroethane in feed for 13 weeks; the results were determined to be equivocal, while the female peripheral blood micronucleus test results were negative. In conclusion, 1,1,1-trichloroethane induced nonneoplastic lesions consistent with hyaline droplet nephropathy in male rats. Exposure to 1,1,1-trichloroethane caused decreases in liver weights in female rats and decreases in mean body weights of male and female mice. The no-observed-adverse-effect level (NOAEL) was estimated to be 10,000 ppm for male and female rats and mice.

Journal Article↗
PubMed2002

NTP Technical Report on the Toxicology and Carcinogenesis Studies of Chloral Hydrate (Cas No. 302-17-0) in B6C3F1 mice (Gavage Studies).

Chloral hydrate is used medically as a sedative or hypnotic and as a rubefacient in topical preparations, and it is often given to children as a sedative during dental and other medical procedures. Chloral hydrate is used as a central nervous system depressant and sedative in veterinary medicine and as a general anesthetic in cattle and horses. It is a byproduct of the chlorination of water and has been detected in plant effluent after the bleaching of softwood pulp. Chloral, the anhydrous form of chloral hydrate, is used as a synthetic intermediate in the production of insecticides and herbicides. Chloral hydrate was nominated for study by the Food and Drug Administration based upon widespread human exposure and its potential hepatotoxicity and the toxicity of related chemicals. One goal of the study was to assess the effect of the animal’s age and the duration of dosing on the tumorigenicity of chloral hydrate. Beginning on postnatal day 28, female B6C3F1 mice received chloral hydrate (99.5% pure) in water by gavage for 3, 6, or 12 months, 2 years, or as a single dose; on postnatal day 15, male and female B6C3F1 mice received a single dose by gavage. Tumorigenicity was assessed for 2 years after the initial dose. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, Drosophila melanogaster, and mouse bone marrow cells. 2-YEAR STUDY Groups of female mice (regimens A, B, C, and D) and groups of male mice (regimen E) received chloral hydrate in distilled water by gavage; control groups received distilled water only. In regimen A, groups of 48 female mice received 0, 25, 50, or 100 mg chloral hydrate/kg body weight 5 days per week for 104 weeks beginning when they were 28 days old. In regimen B, 24 female mice received 0 mg/kg and three groups of 48 female mice received 100 mg/kg 5 days per week beginning when they were 28 days old. Eight mice from the 0 and 100 mg/kg groups were killed at 3, 6, or 12 months. The remaining mice were held without dosing for the duration of the 2-year study. In regimen C, groups of 48 female mice received a single dose of 0, 10, 25, or 50 mg/kg when they were 28 days old and were held for 104 weeks. In regimens D and E, groups of 48 female and 48 male mice, respectively, received a single dose of 0, 10, 25 or 50 mg/kg when they were 15 days old and were held for 104 weeks. Additional groups of four mice from regimens C, D, and E and mice killed at 3 or 6 months from regimen B (eight mice per group) were designated for hepatic cell proliferation analyses; mice killed at 3 or 6 months in regimen B were also designated for apoptosis analyses. Survival and Body Weights Survival of all dosed mice in all regimens was similar to that of the vehicle control groups. Mean body weights of 100 mg/kg female mice in regimen B dosed for 3 or 6 months were generally greater than those of the vehicle controls during the second year of the study. Mean body weights of 25 mg/kg male mice in regimen E were generally less than those of the controls beginning at week 19; mean body weights of 10 and 50 mg/kg mice were generally less than those of the vehicle controls beginning at week 80. Pathology Findings A dose-related and significant increase in the incidence of pars distalis adenoma occurred in regimen A 100 mg/kg females. There was also a time-related increase in the incidence of adenoma in female mice administered 100 mg/kg for up to 24 months in regimen B, and the increase in the incidence of this neoplasm at 24 months was significant. There was a significant increase in the severity of pars distalis hyperplasia in regimen A 100 mg/kg female mice. GENETIC TOXICOLOGY Chloral hydrate was mutagenic in vitro and in vivo. It induced mutations in Salmonella typhimurium strain TA100, with and without liver S9 activation; an equivocal response was obtained in S. typhimurium strain TA98 in the absence of S9, and no mutagenicity was detected with strain TA1535 or TA1537, with or without S9. Chloral hydrate was shown to produce chromosomal damage in mammalian cells. It induced significant increases in sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells, with and without S9. Results of sexlinked recessive lethal (SLRL) tests in Drosophila melanogaster were inconclusive. Chloral hydrate, administered by feeding, produced an inconclusive increase in SLRL mutations in the germ cells of male flies. Results of an in vivo mouse bone marrow micronucleus test with chloral hydrate were positive. CONCLUSIONS Under the conditions of this 2-year gavage study, there was equivocal evidence of carcinogenic activity of chloral hydrate in female B6C3F1 mice treated continuously for two years based on increased incidences of pituitary gland pars distalis adenomas. No increased incidences of neoplasms were seen in female B6C3F1 mice that received a single dose of chloral hydrate at 15 or 28 days of age or in male B6C3F1 mice that received a single dose of chloral hydrate at 15 days of age. No hepatocarcinogenicity was seen under any dosing condition.

Adenoma↗
PubMed1998

NTP Technical Report on the Toxicity Studies of 3,3',4,4'-Tetrachloroazobenzene (CAS No. 14047-09-7) Administered by Gavage to F344/N Rats and B6C3F1 Mice.

3,3',4,4'-Tetrachloroazobenzene is not commercially manufactured but is formed as an unwanted byproduct in the manufacture of 3,4-dichloroaniline and its herbicidal derivatives Propanil(R), Linuron(R), and Diuron(R). In addition, environmental contamination by 3,3',4,4'-tetrachloroazobenzene occurs from the degradation of chloranilide herbicides and the photolysis and biolysis of 3,4-dichloroaniline. 3,3',4,4'-Tetrachloroazobenzene was nominated by the United States Environmental Protection Agency for toxicity testing based on concerns over the potential for human exposure, the structural resemblance to 2,3,7,8-tetrachlorodibenzo-p-dioxin, and the reported dioxin-like effects of 3,3',4,4'-tetrachloroazobenzene. The toxicity of 3,3',4,4'- tetrachloroazobenzene was evaluated in 16-day and 13-week gavage studies in male and female F344/N rats and B6C3F1 mice. In addition to histopathology, evaluations included hematology (rats only), clinical chemistry, thyroid hormone analyses (rats only), cytochrome P(450)1A immunohistochemical staining in the liver (rats only), and assessments of male reproductive endpoints and estrous cycle length. Genetic toxicology studies included mutagenicity tests in Salmonella typhimurium and the determination of micronuclei in mouse bone marrow and peripheral blood erythrocytes. In the 16-day studies, groups of five male and five female rats received 3,3',4,4'-Tetrachloroazobenzene in corn oil by gavage 5 days a week at doses of 0, 12.5, 32, 80, 200, or 500 mg per kg body weight. Groups of five male and five female mice received 3,3',4,4'-Tetrachloroazobenzene in corn oil by gavage 5 days a week at doses of 0, 1, 3.2, 10, 32, or 100 mg/kg. Major effects included increases in liver, lung, and spleen weights of rats and liver and heart weights of mice and decreases in thymus weights of rats and mice. No effects were found on survival or mean body weight gains of rats or mice. Incidences of hematopoietic cell proliferation in the spleen were increased in all groups of dosed male rats, in female rats that received 32 mg/kg or greater, and in 100 mg/kg male and female mice. Renal tubule hyaline droplet accumulation in the cytoplasm of renal cortical epithelial cells and chronic nephropathy were observed microscopically in male rats in the 80, 200, and 500 mg/kg groups. Female mice in the 100 mg/kg group had atrophy of the thymus. In the 13-week studies, groups of 10 male and 10 female rats and mice received 3,3',4,4'-Tetrachloroazobenzene in corn oil by gavage 5 days a week at doses of 0, 0.1, 1, 3, 10, or 30 mg/kg. In the 13-week rat study, the major effects included a decrease in the mean body weight gain of 30 mg/kg females and final mean body weights of 30 mg/kg males and females, decreased thymus weights of males and females in the 10 and 30 mg/kg groups accompanied by thymic atrophy observed microscopically, increased incidences of hematopoietic cell proliferation in the spleen in 10 and 30 mg/kg males and females, a responsive anemia in 10 and 30 mg/kg males and females at week 13, and decreased platelet counts in 10 and 30 mg/kg males and females on day 21 and at week 13. Spleen weights were increased in 10 and 30 mg/kg males and females. Liver weights were increased in males that received 1 mg/kg or greater and in 10 and 30 mg/kg females. Furthermore, hepatic cytochrome P(450)1A staining presence and intensity were increased in 30 mg/kg males and females. Sharp decreases in circulating thyroxine concentrations were observed in males and females at all doses. In spite of this sharp decrease, thyroid-stimulating hormone concentrations were marginally increased. Incidences of hyperplasia of the forestomach were increased in males administered 3 mg/kg or greater and females administered 30 mg/kg. In the 13-week mouse study, the major effects included increases in liver and spleen weights of 10 and 30 mg/kg males and females and increased incidences of hyperplasia of the forestomach in males and females that received 1 mg/kg or greater. Furthermore, a decrease in thymus weight of 30 mg/kg males, an increase in centrilobular hypertrophy of hepatocytes in males that received 3 mg/kg or greater, and an increase in the incidences of hematopoietic cell proliferation in the spleen in males that received 3 mg/kg or greater were observed. A significant decrease in epididymal spermatozoal concentration was observed in 3 and 30 mg/kg males. 3,3',4,4'-Tetrachloroazobenzene was mutagenic in S. typhimurium strain TA97 in the presence of rat liver S9 activation enzymes; no mutagenic activity was detected in strain TA98, TA100, TA1535, or TA1537 with or without S9. In vivo, the frequency of micronucleated erythrocytes was significantly increased in peripheral blood samples from male and female mice given 3,3',4,4'-Tetrachloroazobenzene by gavage for 13 weeks. However, results of a 3-day exposure of up to 200 mg/kg by intraperitoneal injection did not demonstrate induction of micronuclei in bone marrow erythrocytes of male mice. In summary, 3,3',4,4'-Tetrachloroazobenzene caused typical dioxin-like effects, such as thymic atrophy, an increase in liver weights, induction of hepatic cytochrome P(450)1A, and decreased mean body weight gains. Furthermore, in the 13-week studies, a sharp decrease in circulating thyroxine concentrations was observed even at the lowest dose (0.1 mg/kg) tested in rats. Other effects included a decrease in epididymal spermatozoal concentration in mice, major effects on the hematopoietic system, and increased incidences of hyperplasia of the forestomach in 3 and 30 mg/kg males and 30 mg/kg females. A no-observable-adverse-effect-level (NOAEL) was not reached in rats. The NOAEL in mice was 0.1 mg/kg. Comparison of various dioxin-like effects in these studies with those reported in the literature indicate that 3,3',4,4'-Tetrachloroazobenzene is six to two orders of magnitude less potent than 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Journal Article↗
PubMed1998

NTP Technical Report on the Toxicity Studies of 3,3',4,4'-Tetrachloroazoxybenzene (CAS No. 21232-47-3) Administered by Gavage to F344/N Rats and B6C3F1 Mice.

3,3',4,4'-Tetrachloroazoxybenzene is not commercially manufactured but is present as a contaminant of 3,4-dichloroaniline and its herbicidal derivative Diuron(R). In addition, environmental contamination occurs when 3,3',4,4'-tetrachloroazoxybenzene is formed by the photolysis and biolysis of 3,4-dichloroaniline. 3,3',4,4'-Tetrachloroazoxybenzene was nominated by the United States Environmental Protection Agency for toxicity testing based on concerns over the potential for human exposure, the structural resemblance to 2,3,7,8-tetrachlorodibenzo-p-dioxin, and the reported dioxin-like effects of 3,3',4,4'-tetrachloroazoxybenzene. The toxicity of 3,3',4,4'-tetrachloroazoxybenzene was evaluated in 16-day and 13-week gavage studies in male and female F344/N rats and B6C3F1 mice. In addition to histopathology, evaluations included hematology (rats only), clinical chemistry, thyroid hormone analyses (rats only), hepatic cell proliferation (rats only), cytochrome P(450)1A immunohistological staining in the liver (rats only), and assessments of male reproductive endpoints and estrous cycle length. Additional genetic toxicology studies included mutagenicity tests in Salmonella typhimurium and the determination of micronuclei in mouse bone marrow and peripheral blood erythrocytes. In the 16-day studies, groups of five male and five female rats received 3,3',4,4'-tetrachloroazoxybenzene in corn oil by gavage at doses of 0, 12.5, 32, 80, 200, or 500 mg per kg body weight, 5 days a week. Groups of five male and five female mice received 0, 1, 3.2, 10, 32, or 100 mg/kg in corn oil by gavage, 5 days a week. Major effects in rats included increases in liver and lung weights, and decreases in mean body weights and body weight gains, heart weights, and thymus weights. Effects in mice included increases in liver weights and decreases in thymus weights. No effects on survival were observed. Treatment-related lesions included cytoplasmic alteration of hepatocytes, splenic hematopoietic cell proliferation, thymic atrophy, and nephropathy in rats and thymic atrophy, splenic hematopoietic cell proliferation, and hepatic foci of inflammation and necrosis in mice. In the 13-week studies, groups of 10 male and 10 female rats and mice received 3,3',4,4'- tetrachloroazoxybenzene in corn oil by gavage at doses of 0, 0.1, 1, 3, 10, or 30 mg/kg, 5 days a week. In the 13-week rat study, all males and seven females in the 30 mg/kg groups died. Decreases in final mean body weights and body weight gains were observed in 3 and 10 mg/kg males and 10 and 30 mg/kg females. Decreased thymus weights, accompanied by thymic atrophy observed microscopically, were observed at doses of 1 mg/kg or greater in males and females. Increased liver weights were observed in males and females administered 1 mg/kg or greater, and hepatic cytochrome P(450)1A staining was increased in 1 and 3 mg/kg males and 3, 10, and 30 mg/kg females. In addition, a responsive anemia and decreases in platelet counts were observed in dosed male and female rats. A marked decrease in circulating thyroxine concentrations was observed in dosed males and females. In spite of this sharp decrease, thyroid-stimulating hormone concentrations were marginally increased. A decrease in epididymal spermatozoal motility was observed in all dosed groups tested. In 10 mg/kg females, the estrous cycle length was increased. Major effects included increased incidences of hyperplasia of the forestomach in 3, 10, and 30 mg/kg males and 10 and 30 mg/kg females. Increased incidences of centrilobular degeneration and hematopoietic cell proliferation were observed in the liver of dosed males and females. Furthermore, chronic active inflammation of the lung vasculature and hematopoietic cell proliferation in the spleen were observed in dosed males and females. The increased severities of cardiomyopathy and nephropathy in males and the incidences of cardiomyopathy and nephropathy and severity of cardiomyopathy in females were 3,3',4,4'-tetrachloroazoxybenzene related. In the 13-week mouse study, the major effects included increases in liver weights in males administered 3 mg/kg or greater and females administered 1 mg/kg or greater. Hyperplasia of the forestomach and dilatation of hair follicles were observed in 10 and 30 mg/kg males and 30 mg/kg females. Furthermore, thymus weights were decreased in males administered 3 mg/kg or greater and in 10 and 30 mg/kg females. Increased incidences of centrilobular hypertrophy of hepatocytes were observed in 10 and 30 mg/kg males and females. Increased incidences of hematopoietic cell proliferation in the spleen were observed in 30 mg/kg males and in 10 and 30 mg/kg females. Increases in the incidences of thymocyte necrosis were observed in 10 mg/kg males and in 10 and 30 mg/kg females. The incidences of splenic pigmentation were increased in all dosed groups of males, and the severity of pigmentation increased with increasing dose in males and females. 3,3',4,4'-Tetrachloroazoxybenzene was not mutagenic in S. typhimurium strain TA97, TA98, TA100, or TA1535 with or without induced S9 metabolic activation enzymes. It did not induce significant increases in micronucleated erythrocytes in a three-exposure male mouse bone marrow micronucleus test up to dose levels of 200 mg/kg, but results of a 13-week peripheral blood micronucleus test conducted in male and female mice were positive. In summary, 3,3',4,4'-tetrachloroazoxybenzene caused typical dioxin-like effects, including thymic atrophy, increased liver weights, induction of hepatic cytochrome P(450)1A, and decreased mean body weight gains. Furthermore, a marked decrease in circulating thyroxine concentrations was observed in male and female rats, even at the lowest dose (0.1 mg/kg) in female rats. A decrease in epididymal sperm motility was observed at all doses in rats. Effects on the hematopoietic system occurred at doses including and lower than those that caused histopathologic alterations in the liver. A no-observable-adverse-effect-level (NOAEL) was not reached in rats. In male and female mice, the NOAEL was 1 and 0.1 mg/kg, respectively. Furthermore, treatment-related effects included increased incidences of hyperplasia of the forestomach epithelium in rats and mice, chronic active inflammation of the vasculature of the lung in rats, increased incidences and/or severities of cardiomyopathy and nephropathy in rats, and dilatation of the hair follicles in mice. Comparison of various dioxin-like effects in these studies with those reported in the literature indicate that 3,3',4,4'- tetrachloroazoxybenzene is six to two orders of magnitude less potent than 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Journal Article↗
PubMed2002

NTP Technical Report on the toxicity studies of trans-1,2-dichloroethylene (CAS no. 156-60-5) administered in microcapsules in feed to F344/N rats and B6C3F(1) mice.

1,2-Dichloroethylene exists in two isomeric states: trans-1,2-dichloroethylene and cis-1,2-dichloroethylene. The trans isomer is used more widely in industry than the cis isomer. trans-1,2-Dichloroethylene is used as a solvent for waxes, resins, and acetylcellulose. It is also used in the extraction of rubber, as a refrigerant, and in the manufacture of pharmaceuticals and artificial pearls. F344/N rats and B6C3F1 mice were administered trans-1,2-dichloroethylene in microcapsules in feed for 14 weeks. Animals were evaluated for clinical pathology, reproductive system effects, and histopathology. Genetic toxicity studies were conducted in vitro in Salmonella typhimurium and Chinese hamster ovary (CHO) cells, and in vivo in mouse bone marrow cells and peripheral blood erythrocytes. In the 14-week feed studies, groups of 10 male and 10 female rats and mice were fed diets containing microcapsules with a chemical load of 45% trans-1,2-dichloroethylene. Dietary concentrations of 3,125, 6,250, 12,500, 25,000, and 50,000 ppm microencapsulated trans-1,2-dichloroethylene resulted in average daily doses of 190, 380, 770, 1,540, and 3,210 mg/kg for male rats; 190, 395, 780, 1,580, and 3,245 mg/kg for female rats; 480, 920, 1,900, 3,850, and 8,065 mg/kg for male mice; and 450, 915, 1,830, 3,760, and 7,925 mg/kg for female mice. Additional groups of 10 male and 10 female rats and mice served as untreated and vehicle controls. There were no exposure-related deaths of rats or mice. Mean body weights of male rats and male and female mice in the 50,000 ppm groups were significantly less than those of the vehicle controls. The mean body weight gains of female mice in the 12,500 and 25,000 ppm groups were also significantly less than that of the vehicle controls. On day 21 and at week 14, there were mild decreases in hematocrit values, hemoglobin concentrations, and erythrocyte counts in groups of male and female rats in the 25,000 and 50,000 ppm groups. At week 14, these effects were seen in male rats exposed to 6,250 and 12,500 ppm. There were no exposure-related alterations in clinical chemistry parameters in rats or mice. The liver weights of female rats exposed to 6,250 ppm or greater were significantly greater than those of the vehicle controls. The absolute kidney weights of male rats exposed to 25,000 or 50,000 ppm were significantly decreased. No gross or microscopic lesions were observed in rats or mice that could be attributed to trans-1,2-dichloroethylene exposure. Neither cis-, trans-, nor cis,trans-1,2-dichloroethylene was mutagenic in S. typhimurium strain TA97 (cis isomer only), TA98, TA100, TA1535, or TA1537, with or without S9 metabolic activation enzymes. In CHO cells in vitro, cis- 1,2-dichloroethylene induced sister chromatid exchanges (SCEs) in the absence of S9; with S9, the single trial that was performed yielded equivocal results. The cis,trans isomer induced significant increases in SCEs in cultured CHO cells with and without S9. In contrast to these positive results, trans-1,2-dichloroethylene gave negative results in the SCE test, with and without S9. Neither cis-, trans-, nor cis,trans-1,2-dichloroethylene induced chromosomal aberrations (Abs) in cultured CHO cells, with or without S9. In vivo, no induction of SCEs or Abs was noted in bone marrow cells of male mice administered cis- or trans-1,2-dichloroethylene by intraperitoneal injection once, with sampling performed 23 hours (for SCE analyses) or 17 hours (for Abs analyses) after injection. In addition, negative results were obtained in a peripheral blood micronucleus test in male and female mice administered trans- 1,2-dichloroethylene in microcapsules in feed for 14 weeks. Very little toxicity was associated with ingestion of microencapsulated trans-1-2-dichloroethylene. Histopathology and clinical chemistry data, combined with body and organ weight data, revealed that the maximum tolerated dose was not reached in these studies.

Animals↗
PubMed1991

NTP technical report on the toxicity studies of D&C Yellow No. 11 in F344/N Rats and B6C3F1 Mice (Feed Studies) (CAS No. 8003-22-3).

Toxicity studies were conducted by administering D&C Yellow No. 11 (approximately 99%percnt; pure) in feed at dietary concentrations of up to 50,000 ppm to groups of F344/N rats and B6C3F1 mice of each sex for 14 days or 13 weeks. A separate study was conducted to determine the effects of feeding diets containing D&C Yellow No. 11 to female rats during a reproductive cycle and to their offspring. Although the estimated intake of D&C Yellow No. 11 by mice was more than twice that by rats, the results of the 14-day and 13- week studies were similar for both rats and mice. In both species, D&C Yellow No. 11 caused no deaths (5 animals per group in the 14- day studies and 10 per group in the 13-week studies) but did reduce body weight gain slightly in rats of each sex exposed to 17,000 or 50,000 ppm. Liver weights were increased in dosed rats and mice. There was minimal-to-mild degeneration of the periportal portion of the liver lobules of rats at dietary concentrations of 1,700 ppm and higher and of mice at 5,000 ppm and higher. A dose- related yellow-brown pigment was observed in hepatocytes, Kupffer cells, and biliary epithelium of the liver of each sex and species and in the tubular epithelium of the kidney of rats of each sex. Hepatocellular degeneration progressed slightly in severity with increased time of exposure (i.e., 14 days to 13 weeks) in rats but not in mice. The number and size of hyaline droplets in the tubular epithelium of the cortex and outer medulla of the kidney were increased in all dosed groups of male rats. In a perinatal toxicity study, body weight gain of rat dams given diets containing as much as 50,000 ppm D&C Yellow No. 11 for 4 weeks before mating to unexposed males was similar to that of controls at the time of mating but was lower at parturition and weaning. However, fertility, gestation length, litter size, and pup birth weights were unaffected by exposure. At weaning, body weights of pups from all dosed dams (5,000, 17,000, and 50,000 ppm) were lower than weights of pups from the controls. After exposure to DC Yellow No. 11 for 4 weeks through the milk and to feed containing the same dietary concentrations that the dams received, weights of the 5,000-ppm pups were similar to those of the controls, but weights of the 17,000- and 50,000-ppm dose groups remained depressed. Microscopic evaluation showed lesions in the pups in all dosed groups; these lesions were similar to those described in the liver and kidney of rats in the 14-day and 13-week studies, including the male rat kidney cytoplasmic alterations. The results of these studies indicate that compound-related effects occurred at all dietary concentrations of DC Yellow No. 11; i.e., liver weights were increased in dosed rats and mice, and there was an increase in the number and size of hyaline droplets in all dosed groups of male rats. Synonyms: 2-(2-quinolyl)-1,3-indanedione; Arlosol Yellow S; Chinoline Yellow D soluble in spirits; Chinoline ZSS; CI 47000; C.I. Solvent Yellow 33; Nitro Fast Yellow SL; Oil Yellow SIS; Petrol Yellow C; Quinolin Yellow A Spirit Soluble; Quinoline Yellow Base; Quinoline Yellow Spirit Soluble; Quinoline Yellow SS; Solvent Yellow 33; Waxoline Yellow T.

Journal Article↗
PubMed1991

NTP technical report on the toxicity studies of 1,2,4,5-Tetrachlorobenzene in F344/N Rats and B6C3F1 Mice (Feed Studies) (CAS No. 95-94-3).

Toxicology studies were conducted by exposing groups of F344/N rats and B6C3F1 mice of each sex to 1,2,4,5-tetrachlorobenzene (greater than 99%percnt; pure) at various concentrations in formulated diets for 14 days or 13 weeks. Dietary concentrations were 0, 30, 100, 300, 1,000, or 3,000 ppm 1,2,4,5-tetrachlorobenzene in the 14 day studies. All rats survived to the end of the studies, but all mice in the 3,000-ppm groups died (five animals per group). Histologically, exposed male rats had an accumulation of abnormal hyaline droplets in the renal cortical epithelium. Significant histologic lesions were not seen in female rats or in mice of either sex. Dietary concentrations were 0, 30, 100, 300, 1,000, or 2,000 ppm 1,2,4,5-tetrachlorobenzene in the 13-week studies (10 animals per group). All rats survived to the end of the studies; two female mice in the 2,000-ppm group were killed in a moribund condition. Body weight gains in the higher dose groups of rats and mice were less than those of controls. In exposed male rats, lesions included renal cortical tubular epithelial hyaline droplet formation, cortical tubular regeneration, and medullary granular casts and mineralization. This spectrum of renal lesions in male rats is consistent with the entity described as "hydrocarbon or hyaline droplet nephropathy." In some exposed female rats (30- to 2,000-ppm groups), there was renal cortical tubular cell regeneration plus accumulation of an unidentified yellow-brown pigment in the renal cortical epithelium. Centrilobular hepatocellular hypertrophy was observed in the livers of exposed male and female rats. In mice, minimal-to-mild centrilobular hepatocellular hypertrophy was present in males in the 1,000 and 2,000-ppm groups and in females in the 2,000-ppm group. Minimal-to-mild individual hepatocyte degeneration occurred in mice of each sex in the 2,000-ppm groups. Increased serum sorbitol dehydrogenase and alanine aminotransferase activity was observed in the two highest dose groups of male and female mice and indicated hepatocellular injury. Thyroid follicular cell hypertrophy was present in male rats in the 300- to 2,000-ppm groups and in female rats in the 100- to 2,000-ppm groups. Decreased free thyroxin and total thyroxin concentrations in male rats in the 300- to 2,000 ppm groups and female rats in the 30- to 2,000-ppm groups indicated a primary hypothyroid state. Hematologic findings for rats that received 1,000 or 2,000 ppm included significantly decreased hematocrit values, hemoglobin concentration, and erythrocyte counts for males and decreased mean cell volume for females; for mice, decreased hemoglobin concentrations, mean corpuscular hemoglobin, hematocrit, and mean cell volume were observed in males in the 2,000-ppm group and in females in the 1,000- and 2,000-ppm groups. These findings suggest a poorly regenerative anemia in both species. The no-observed-effect level (NOEL) for histologic lesions was 30 ppm for male and female rats. The NOEL for histologic lesions in male and female mice was 300 ppm. Synonyms: s-tetrachlorobenzene; benzene tetrachloride. (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↗
PubMed1991

NTP technical report on the toxicity studies of Pentachlorobenzene in F344/N Rats and B6C3F1 Mice (Feed Studies) (CAS No. 608-93-5).

Toxicology studies were conducted by exposing groups of F344/N rats and B6C3F1 mice of each sex to pentachlorobenzene (99%percnt; pure) in feed for 15 days or 13 weeks. Exposure concentrations were 0, 100, 330, 1,000, 3,300, or 10,000 ppm pentachlorobenzene in the 15-day studies (five animals of each sex per group per species). All rats that received 10,000 ppm and all mice that received 3,300 or 10,000 ppm died. Of the exposed rats that survived to the end of the studies, males had an accumulation of abnormal hyaline droplets in the renal cortical epithelium and males and females had centrilobular hepatocellular hypertrophy. Chemical-related lesions were not observed in exposed mice. Exposure concentrations were 0, 33, 100, 330, 1,000, or 2,000 ppm pentachlorobenzene in the 13-week studies (10 animals of each sex per group per species). No compound-related deaths occurred. Body weights of exposed rats but not of mice were lower than those of controls. In male rats, dose-related histologic lesions included renal tubular epithelial hyaline droplet formation and medullary granular casts and mineralization. This spectrum of renal lesions in male rats is consistent with the entity described as "hydrocarbon or hyaline droplet nephropathy." Exacerbation of spontaneous nephropathy characterized by renal tubular cell regeneration and homogeneous intratubular protein casts was seen in rats of each sex. Urinary protein concentration was increased in male and female rats in the 1,000- and 2,000-ppm groups; this change was especially prominent in males. Urinary glucose concentration was increased in male rats in the 330- to 2,000-ppm groups and in female rats in the 1,000 and 2,000-ppm groups. Centrilobular hepatocellular hypertrophy was observed in exposed male and female rats. Unidentified yellow-brown pigment granules were present in hepatocytes and renal tubular epithelium in exposed animals of each sex but were more prominent in females. These granules possibly contained porphyrins. The only exposure-related histologic lesion in mice of either sex was centrilobular hepatocellular hypertrophy. Significant, but not dose-related, increases of liver porphyrin concentrations were observed in exposed male rats; female rats in the 2,000-ppm group also had increased liver porphyrin concentrations. Liver porphyrin concentrations were significantly increased in the 1,000- and 2,000-ppm groups of mice of each sex. Increased sorbitol dehydrogenase concentrations in exposed rats and mice of each sex were attributed to mild hepatocyte injury. Minimal thyroid follicular cell hypertrophy was also present in male and female rats in the 1,000 and 2,000-ppm groups. Free thyroxin and total thyroxin concentrations were significantly decreased in exposed male and female rats; these data indicate moderate hypothyroxinemia in exposed animals. Hematologic findings in exposed rats included decreased hematocrit, hemoglobin concentration, erythrocyte count (males), mean corpuscular hemoglobin, mean erythrocyte volume, and mean corpuscular hemoglobin concentration; these findings are consistent with a mild-to-moderate anemia that is microcytic (decreased mean cell volume), hypochromic (decreased mean corpuscular hemoglobin concentration, females), and poorly regenerative (slight-to-no change in reticulocyte counts). The no-observed effect levels (NOELs) for histologic lesions were 33 ppm for male rats and 330 ppm for female rats. The NOEL for histologic lesions in female mice was 100 ppm. An NOEL was not reached for male mice. Synonyms: 1,2,3,4,5-Pentachlorobenzene; quintochlorobenzene. (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↗
PubMed1991

NTP technical report on the toxicity studies of Cobalt Sulfate Heptahydrate in F344/N Rats and B6C3F1 Mice (Inhalation Studies) (CAS No. 10026-24-1).

Toxicology studies of cobalt sulfate heptahydrate (99%percnt; pure) were conducted by exposing groups of F344/N rats and B6C3F1 mice of each sex to a cobalt sulfate heptahydrate aerosol 6 hours per day, 5 days per week, for 16 days or 13 weeks. In 16-day studies, all rats and mice exposed at the top concentration of 200 mg cobalt sulfate/m3 died (5 animals per group); partial survival was seen in the 50 mg/m(3) exposure groups. Degeneration of the olfactory epithelium and necrotizing inflammation occurred in the nose of all rats and mice that died and in animals exposed to 50 mg/m(3). Necrotizing inflammation was observed in the larynx and trachea of rats and mice at concentrations as low as 5 mg/m(3), and a similar lesion was present in the bronchi at exposure concentrations of 50 mg/m(3) or higher. Regenerative and inflammatory lesions, including peribronchial and septal fibrosis in the lung, were found in rats and mice exposed to 50 mg/m(3). In 13-week studies, all rats, all female mice, and all but 2 male mice exposed at the top concentration survived to the end of the studies (target exposure concentrations of 0, 0.3, 1, 3, 10, and 30 mg/m(3), 10 animals per group). Rats and mice exposed to 30 mg/m(3) lost weight during the first exposure week and then gained weight at the same rate as controls. Lung weights were increased over those of controls in rats exposed at concentrations as low as 1 mg/m(3) and in mice exposed to 10 mg/m(3) or more. Polycythemia was observed in rats exposed to cobalt sulfate but not in mice. Sperm motility was decreased in mice exposed at 3 mg/m(3) or at higher concentrations (lower concentrations were not evaluated), and increased numbers of abnormal sperm were found in mice exposed to 30 mg/m(3). Testis and epididymal weights were decreased in mice exposed to 30 mg/m(3). Cobalt content in the urine of rats increased with increasing atmospheric cobalt exposure. Lesions seen in the respiratory tract in 13-week studies in rats and mice included degeneration of the olfactory epithelium, squamous metaplasia of the respiratory epithelium, and inflammation in the nose; inflammation, necrosis, squamous metaplasia, ulcers (rats), and inflammatory polyps (rats) of the larynx; squamous metaplasia of the trachea (mice); and histiocytic infiltrates, bronchiolar regeneration, peribronchiolar and septal fibrosis, and epithelial hyperplasia in the alveoli of the lung. The most sensitive tissue was the larynx, with squamous metaplasia observed in rats and mice at the lowest exposure concentration of 0.3 mg/m(3). Thus, a no-observed-adverse-effect level was not reached in these studies. (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↗
PubMed1991

NTP technical report on the toxicity studies of 1,2-Dichloroethane (Ethylene Dichloride) in F344/N Rats, Sprague Dawley Rats, Osborne-Mendel Rats, and B6C3F1 Mice (Drinking Water and Gavage Studies) (CAS No. 107-06-2).

Thirteen-week studies were conducted to investigate potential differences in rat strain susceptibility to 1,2-dichloroethane toxicity. F344/N rats, Sprague Dawley rats, Osborne-Mendel rats, and B6C3F1 mice (10 animals of each sex) were exposed to 1,2- dichloroethane in drinking water at 0, 500, 1,000, 2,000, 4,000, or 8,000 ppm for 13 weeks. In addition, Groups of 10 F344/N rats of each sex were administered 1,2-dichloroethane in corn oil by gavage to compare toxicity resulting from bolus administration with that of continuous exposure in drinking water. Gavage doses of 1,2-dichloroethane were within the range of daily doses resulting from exposure in drinking water. No compound-related deaths occurred in any of the rat strains exposed to 1,2-dichloroethane in drinking water. Weight gain depression was common in each sex of all three rat strains in the 4,000 and 8,000-ppm groups throughout the studies. Water consumption was decreased by 50%-60% with increasing dose for all exposed male and female rats regardless of strain. Kidney and liver weights were increased in dosed rats of all three strains. No chemical-related lesions were observed except for a dose- related incidence of renal tubular regeneration in female F344/N rats. Nine of 10 female mice exposed to 8,000 ppm 1,2-dichloroethane in drinking water died before the end of the study. Mean body weights of males at 500 ppm or more and females at 1,000 ppm or more were lower than those of controls throughout most of the studies. Kidney weights were significantly increased for dosed males and females. Renal tubular cell regeneration was seen in males at 8,000 ppm; at 4,000 ppm, minimal regeneration was present in 8/10 male mice. All male F344/N rats that received 240 or 480 mg/kg and 9/10 females that received 300 mg/kg 1,2-dichloroethane by gavage died before the end of the studies. Mean body weights of the highest dose males and females were lower than those of vehicle controls throughout the studies. Liver and kidney weights were increased for dosed males and females; however, no compound-related lesions were observed. Necrosis of the cerebellum, hyperplasia, inflammation, and mineralization of the forestomach, and necrosis of the thymus were seen in animals that died or were killed in moribund condition. Rat strain differences in susceptibility to 1,2-dichloroethane toxicity were not apparent at the drinking water concentrations used in these studies; only female F344/N rats exhibited mild chemical related renal lesions. Male B6C3FI mice appeared to be more susceptible than rats to toxicity of 1,2-dichloroethane administered in drinking water; renal tubule regeneration was observed in male mice in the 4,000- and 8,000-ppm groups. The higher toxicity in mice was likely due to higher water consumption, resulting in up to tenfold higher doses to mice than to rats. 1,2-Dichloroethane administered in drinking water resulted in less toxicity to F344/N rats than administration of similar doses by gavage. Synonyms: Freon 150; Brocide; Dutch liquid; Dutch oil. (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↗
PubMed1991

NTP technical report on the toxicity studies of Acetone in F344/N Rats and B6C3F1 Mice (Drinking Water Studies) (CAS No. 67-64-1).

Toxicity studies were conducted by administering acetone (greater than 99%percnt; pure) in drinking water to groups of F344/N rats and B6C3F1 mice of each sex for 14 days or 13 weeks. Fourteen-Day Studies: All rats and mice receiving concentrations as high as 100,000 ppm acetone in drinking water lived to the end of the 14-day studies. The mean body weights of male rats receiving 50,000 or 100,000 ppm and female rats given 100,000 ppm were lower than those of controls. Body weights of all groups of mice were similar. Kidney and liver weight to body weight ratios for exposed rats and mice were greater than those for controls. Histopathologic changes were not seen in these organs in rats or in the kidney in mice. Centrilobular hepatocellular hypertrophy was noted in male and female mice receiving 20,000 and 50,000 ppm acetone, respectively. Thirteen-Week Studies: All rats lived to the end of the 13-week studies (drinking water concentrations as high as 50,000 ppm). The final mean body weights of rats receiving 50,000 ppm were 19%percnt; lower than that of controls for males and 7%percnt; lower for females. Water consumption by all rats that received 50,000 ppm acetone and females that received 20,000 ppm or more was notably lower than that by controls. Liver and kidney weight to body weight ratios were increased for male and female rats receiving 20,000 ppm or greater. Caudal and right epididymal weights and sperm motility were decreased for male rats given 50,000 ppm, and the percentage of abnormal sperm was increased. Leukocytosis and thrombocytopenia were observed at 20,000 ppm and above (males and females), and reticulocytopenia and erythrocytopenia were seen at 5,000 ppm and above (males). These changes, in addition to increase in erythrocyte size (MCV), are consistent with macrocytic anemia. Splenic pigmentation (hemosiderosis) noted in dosed male rats was apparently related to these changes. The increased incidence and severity of nephropathy observed in dosed male rats were considered the most prominent chemically related findings in this study. All mice lived to the end of the 13-week studies (drinking water concentrations up to 20,000 ppm for males and up to 50,000 ppm for females). The final mean body weights of dosed and control mice were similar. Water consumption by female mice that received 50,000 ppm acetone was notably lower than that by controls. The absolute liver weight and the liver weight to body weight ratio were significantly increased for females receiving 50,000 ppm, and the absolute spleen weight and the spleen weight to body weight ratio were significantly decreased. Results from the hematologic analyses did not show any biologically significant effects. Centrilobular hepatocellular hypertrophy of minimal severity was seen in 2110 female mice receiving 50,000 ppm. No compound-related lesions were found in male mice. In summary, the results from these studies show that acetone is mildly toxic to rats and mice when administered in drinking water for 13 weeks. Minimal toxic doses were estimated to be 20,000 ppm acetone for male rats and male mice and 50,000 ppm acetone for female mice. No toxic effects were identified for female rats. The testis, kidney, and hematopoietic system were identified as target organs in male rats, and the liver was the target organ for male and female mice. Synonyms: 2-propanone; dimethyl ketone; pyroacetic acid. (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.)

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PubMed1991

NTP technical report on the toxicity studies of of n-Hexane in B6C3F1 Mice (Inhalation Studies) (CAS No. 110-54-3).

Thirteen-week inhalation toxicity studies of n-hexane were conducted with B6C3F1 mice of each sex exposed to 0, 500, 1,000, 4,000, or 10,000 ppm, 6 hours per day, 5 days per week or to 1,000 ppm, 22 hours per day (referred to as 1,000c), 5 days per week. All mice lived to the end of the studies. The final mean body weights of mice exposed to 1,000c ppm or 10,000 ppm were 10% or 17% lower than that of the controls for males and 0% or 6% lower for females. Hematologic analyses were performed on whole blood samples collected at the end of the 13-week exposure. Segmented neutrophils were significantly increased in male mice exposed to 10,000 ppm. A battery of behavioral measurements was conducted on mice, and the only parameter affected was locomotor activity, which was decreased in female mice at 1,000c ppm and 10,000 ppm. The test battery performed included forelimb and hind limb grip strength, motor activity and exploratory behavior, acoustic startle response, foot splay, and analgesia response. Compound-related lesions of the nasal turbinates were seen in all groups of exposed mice except males exposed to 500 or 4,000 ppm. At the 10,000-ppm concentration, nasal lesions included inflammatory, erosive, and regenerative lesions of the olfactory and respiratory epithelium; luminal exudation and metaplastic lesions of the olfactory epithelium; and fibrosis of the submucosa. Lymphoid hyperplasia of the mandibular lymph nodes and neutrophilic hyperplasia of the bone marrow were also seen. At lower concentrations, lesions were not present in all mice and were limited to minimal regeneration or metaplasia of the olfactory epithelium. A few paranodal swellings in the teased fibers of the tibial nerve were observed in 3/4 males and 3/4 females exposed to 10,000 ppm, 3/4 males and 3/4 females exposed to 1,000c ppm, and 0/4 male and 0/4 female controls; the severity of the lesions was minimal. Neither segmental demyelination nor distal axonal degeneration was seen. Exposure of mice to n-hexane at concentrations up to 10,000 ppm resulted in only minimal toxicity. Paranodal swellings seen in nerves at 1,000c ppm and at 10,000 ppm were considered to be minimal nerve damage that would not result in paralysis. Exposure- related lesions of the nasal cavity occurred after n-hexane exposure, but minimal or no effects were seen at 1,000 ppm or below. Synonyms: Hexyl hydride. (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.)

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PubMed1991

NTP technical report on the toxicity studies of Hexachloro-1,3-butadiene in B6C3F1 Mice (Feed Studies) (CAS No. 87-68-3).

Two-week and 13-week toxicity studies of hexachloro-1,3-butadiene incorporated in the diet were conducted in B6C3F1 mice. Groups of five mice of each sex received diets containing 0, 30, 100, 300, 1,000, or 3,000 ppm hexachloro-1,3-butadiene for 15 days. Toxic responses in the 2-week studies, primarily in the higher dose groups, included abnormal clinical signs (lethargy, hunched posture, rough hair coats, light sensitivity, and/or in coordination), deaths (all mice in the two highest dose groups died by day 7), body and organ weight depression, and gross and histopathologic changes. The most prevalent microscopic lesion, seen in all hexachloro-1,3-butadiene-dosed mice, was renal tubular cell necrosis and/or regeneration. Regeneration was seen in lower dose groups. In addition to kidney lesions, histopathologic changes were also seen in the liver (hepatocyte necrosis, cytoplasmic vacuolization), lymphoid tissues (lymph node necrosis, depletion), and testis (seminiferous tubule giant cells) of mice in the two highest dose groups which died during the first week of the studies. Thirteen-week studies were conducted in which groups of 10 mice per sex received 0,1, 3,10, 30, or 100 ppm hexachloro-1,3-butadiene in feed (corresponding to doses of 0, 0.1, 0.4, 1.5, 4.9, or 16.8 mg/kg per day for males and 0.2, 0.5, 1.8, 4.5, or 19.2 mg/kg per day for females). No compound-related clinical signs or deaths were observed. Compared with controls, body weight gain was reduced in males receiving 30 and 100 ppm (-49% and -56%, respectively) and females receiving 100 ppm (-47%). Kidney weights were reduced in the males receiving 30 and 100 ppm and females receiving 100 ppm. A compound-related increase in tubular cell regeneration in the renal cortex occurred in male and female mice. This lesion, characterized by a diffuse increase in basophilia of the tubular epithelial cytoplasm and an increase in the number of nuclei, increased in severity with increased dose. The motility of sperm from dosed mice was lower, though not dose related, than that from controls. Female mice were more susceptible to the toxicity of hexachloro-1,3-butadiene than male mice. Based on the histopathologic evaluations, the no-observed-adverse-effect level appeared to be 10 ppm for the male mice in this 13-week study; no such level was identified for the female mice. Synonyms: HCBD; hexachlorobutadiene; 1,1,2,3,4,4-hexachloro-1,3- butadiene; perchlorobutadiene; C 46; Dolen-Pur, (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.)

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PubMed1993

NTP technical report on the toxicity studies of Methyl Ethyl Ketone Peroxide (CAS No. 1338-23-4) in Dimethyl Phthalate (CAS No. 131-11-3) (45:55) Administered Topically in F344/N Rats and B6C3F1 Mice.

Methyl ethyl ketone peroxide (MEKP) is an unstable organic peroxide used in the manufacture of acrylic resins, as a hardening agent for fiberglass-reinforced plastics, and as a curing agent for unsaturated polyester resins. It is commercially available as a 40% to 60% solution in dimethyl phthalate (DMP). Because exposure to MEKP is typically through dermal contact, 2-week and 13-week toxicity studies were conducted by topical application of MEKP in DMP (45:55 w/w) to the clipped dorsal region of male and female Fischer 344/N rats and mice. Animals were evaluated for histopathology and for reproductive endpoints. In vitro genetic toxicity studies of MEKP included assessments of mutagenicity in Salmonella typhimurium and in mouse lymphoma L5178Y cells and analysis of chromosomal aberrations and sister chromatid exchanges in Chinese hamster ovary cells. In addition, the peripheral blood of mice from the 13-week study was evaluated in the micronucleus assay. In the 2-week studies, groups of 5 animals of each species and sex were administered MEKP in DMP for 5 days per week at doses of 50.6, 101.3, 202.5, 405, and 810 mg/kg body weight per day for rats and 112.5, 225, 450, 900, and 1800 mg/kg body weight per day for mice. Control groups received DMP or no treatment. No rats died during the studies, but at least 1 mouse in each group receiving MEKP died. Body weight gains of rats decreased with increasing doses of MEKP; body weight gains of mice were not affected by treatment. The primary effects of topical administration of MEKP in both rats and mice were an extensive coagulative necrosis of the epidermis and dermis, variable degrees of inflammation of the adnexa, and epidermal regeneration and hyperplasia at the application site. Lesions considered secondary to the dermal lesions included increased hematopoiesis in the spleen in rats and mice and increased myeloid hyperplasia of the bone marrow in mice, primarily at the higher doses. Mice showed a marked, dose-related increase in liver weight. In the 13-week dermal studies, groups of 10 rats and 10 mice of each sex were administered MEKP in DMP for 5 days per week at doses of 1.07, 3.57, 10.7, 35.7, and 107 mg/rat and 0.357, 1.19, 3.57, 11.9, and 35.7 mg/mouse. All high-dose mice, 3 high-dose female rats, and 1 female mouse in the 11.9 mg/animal group died or were sacrificed during the first week of the studies. Skin lesions similar to those seen in the 2-week studies were judged of sufficient severity to warrant early termination of surviving rats and mice in the 2 highest dose groups. All rats and mice in the remaining dose groups survived to the end of the studies, and weight gains were generally lower with increasing doses of MEKP. Skin lesions at the application site for the remaining animals (rats and mice) in the 10.7 mg/rat and 3.57 mg/mouse dose groups involved a spectrum of necrosis, inflammation, and acanthosis (epidermal hyperplasia). Lesions in the lower dose groups were limited to acanthosis and hyperkeratosis in rats (1.07 and 3.57 mg/rat) and acanthosis in mice (0.357 and 1.19 mg/mouse). While splenic and bone marrow lesions similar to those described in the 2-week studies were seen in animals that died early in the 13-week studies and in the rats and mice that showed ulcerative or necrotic injury, no other systemic changes were noted in animals that did not show ulcerative skin lesions. In genetic toxicity studies, MEKP in DMP (45:55 w/w) was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, or TA98, with or without S9activation. A positive response was obtained in the mouse lymphoma assay for induction of trifluorothymidine resistance in L5178Y cells without S9. In cytogenetic tests with Chinese hamster ovary cells, MEKP induced sister chromatid exchanges and chromosomal aberrations, with and without S9. No increase in the frequency of micronucleated erythrocytes was observed in peripheral blood samples obtained from male and female mice at the termination of the 13-week toxicity study. In summary, topical administration of MEKP in DM of MEKP in DMP resulted in a spectrum of necrotic, inflammatory, and regenerative skin lesions limited to the application site. Histopathologic changes in the spleen and bone marrow were also seen in rats and mice with ulcerative skin lesions, and were considered a secondary response. A no-observed-adverse-effect level (NOAEL) for histopathologic skin lesions could not be determined from these studies, as lesions were observed with administration of daily doses as low as 1.07 mg for rats and 0.357 mg for mice. Methyl Ethyl Ketone Peroxide Synonyms: 2-Butanone Peroxide. Dimethyl Phthalate Synonyms: 1,2-Benzenedicarboxylic acid dimethyl ester; phthalic acid dimethyl ester; methyl phthalate; dimethyl 1,2-benzene- dicarboxylate; DMP

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PubMed1992

NTP technical report on the toxicity studies of Black Newsprint Inks Administered Topically to F344/N Rats and C3H Mice.

Toxicity studies were conducted by applying black newsprint inks or mineral oils to clipped skin of the dorsal interscapular area of C3H mice and F344/N rats of both sexes, to determine systemic and local effects. Four lots of both letterpress and offset types of newsprint ink were studied, either as composite mixtures or as individual lots. An industrial grade mineral oil, used as an extender for newsprint ink formulation, and USP medicinal grade mineral oil also were studied. Analyses for the presence of polycyclic aromatic hydrocarbons (PAHs) were conducted on composite ink mixtures and mineral oils; letterpress and offset ink mixtures were found to have cumulative concentrations of 206 and 105 ppm, respectively; the concentration of PAHs in the printing ink mineral oil sample was 208 ppm, while none were detected in the USP grade mineral oil. In genetic toxicity studies, letterpress and offset newsprint ink composite mixtures were each mutagenic in Salmonella typhimurium strains TA98 and TA100 when tested in a preincubation protocol with added hamster liver S9. With rat liver S9, results for both inks were positive in strain TA98 and negative in strain TA100. Neither type of ink was mutagenic in the absence of S9 activation. In 30-day studies, 5 rats and mice per sex were given single, daily dermal applications of letterpress or offset newsprint inks, 5 days per week, for a total of 21 - 22 applications. Dose groups for each type of ink received either the neat (undiluted) composite ink mixture, or the 3:1, 1:1, or 1:3 dilutions (ink:USP mineral oil), with a total dose volume of 100 (mice) or 250 (rats) &mgr;l. All animals survived until the end of the studies. Toxicity attributed to ink administration was limited to decreased body weight gains in female rats treated with neat and the 3:1 dilution of letterpress ink, and to scaliness at the site of application in 1 or more mice in each letterpress ink treatment group. As a result of grooming activity and the large amount of test chemical applied, chemicals were spread over the body, and there was evidence that some oral ingestion had occurred. In 13-week studies, various ink and mineral oil formulations were administered dermally to 10 rats and mice per sex. To prevent accumulation of inks and distribution over the body as seen in the 30-day studies, the frequency of application was reduced to twice weekly and the total dose volume was decreased to 20 microliters for mice and 50 microliters for rats. Treatment groups for rats consisted of letterpress ink mixture, offset ink mixture, printing ink mineral oil, USP mineral oil, and clipped, untreated controls. Groups of mice were administered each of the 4 individual lots of both letterpress and offset inks, the composite mixtures of each, and printing ink and USP mineral oils; clipped, untreated groups served as controls. All rats, all male mice, and all female mice except one administered offset ink-lot E survived to the end of the studies. Effects attributable to compound administration in rats were limited to decreased body weight gains in females treated with printing ink mineral oil and letterpress ink mixture, and increased liver and kidney weights in both males and females exposed to USP mineral oil; there were no local toxic effects at the site of application. In mice, there were no body weight effects, but liver weights were increased in most ink and mineral oil treatment groups of both sexes. Dermal toxicity was evidenced in mice by scaliness and irritation at the site of application of both sexes treated with USP mineral oil and letterpress ink-lot C. Microscopically, local toxicity at the site of application was observed in mice of all treatment groups and was characterized by acanthosis and inflammation. In summary, results of these studies indicate that topical administration of black newsprint inks and mineral oils produces local toxicity at the site of application in mice; toxic effects on the skin in this species are consistent with those of a primary cutaneous irritant. In rats, possible evidence for toxicity was limited to decreased body weight gains in females treated with letterpress ink formulations.

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