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PubMed1992

NTP technical report on the toxicity studies of t-Butyl Perbenzoate (CAS No. 614-45-9) Administered By Gavage To F344/N Rats And B6C3F1 Mice.

t-Butyl perbenzoate (t-BP) is a relatively stable, lipid-soluble, organic peroxide widely used in the polymer industry. Studies were designed to determine the stability of t-BP in various biological media, its dermal absorption and distribution in intact animals, and the toxicity of t-BP when administered orally to both sexes of rats and mice for 14 days or 13 weeks. In genetic toxicity studies, t-BP was found to be mutagenic in Salmonella typhimurium strains TA100, TA1537, and TA98, with and without metabolic activation. t-BP-induced sister-chromatid exchange and chromosomal aberrations in Chinese hamster ovary cells in vitro but did not induce formation of micronuclei in peripheral blood in mice in the 13-week studies. Stability studies indicated t-BP was sufficiently stable in dose formulations to permit administration by gavage, intravenous injection, or dermally. However, t-BP degraded rapidly in blood, stomach contents, and liver homogenates, or in the presence of glutathione. Initial degradation products of t-BP are benzoic acid and t-butanol. Studies of t-BP disposition determined that approximately 16% of dermal doses administered to rats was absorbed and rapidly eliminated without tissue accumulation. Similarly, t-BP given intravenously was rapidly degraded and eliminated, primarily in urine, with no apparent accumulation in any tissue. Because dermal absorption was considered insufficient to administer a toxic dose, studies of t-BP toxicity were performed using gavage administration. Results of 14-day toxicity studies with 5 animals of each sex of rats and mice indicated that t-PB, administered by gavage in corn oil in doses ranging from 70 to 1112 mg/kg, produced no marked signs of systemic toxicity. Toxicity in mice, attributable to t- BP, was limited largely to increased stomach weights in males and females receiving the highest doses. This toxicity was characterized by forestomach epithelial hyperplasia, ulceration, and acute inflammation. Equimolar doses of the degradation products of t-BP (t-butanol and benzoic acid) also were administered in the 14-day studies to determine if t-BP toxicity could be attributed to the parent compound or products of its chemical degradation and/or metabolism. Results of these studies indicated that equimolar doses of t-butanol were not toxic in either sex or species. Some systemic toxicity of benzoic acid was observed in both sexes of mice, but not rats, receiving the highest dose (642 mg/kg). Toxicity was evidenced by the poor condition of dosed animals and in several deaths during the first week of the study. No lesions were observed microscopically, and it is speculated that this toxicity may have been due to acidosis. In the 13-week studies, t-BP was administered by gavage in water to 10 rats and 10 mice of each sex, at doses up to 500 mg/kg. The doses resulted in depressed body-weight gains in the highest dose groups and in dose-dependent increases in forestomach weights. Hyperplasia of the forestomach mucosa was observed in most groups of dosed rats and increased in severity with dose. Hyperplasia was characterized by increased cellularity and basophilia of the squamous epithelium with variable degrees of hyperkeratosis. t-BP toxicity observed in mice was limited to increased forestomach weight in most dose groups and to less dramatic increases in glandular stomach weight in mice receiving the highest doses. Forestomach toxicity was characterized by dose-dependent increases in hyperplasia of the squamous epithelium in all mice except those in the low dose group. Based on the results presented in this report, it is concluded that the no-observed-adverse-effect-level (NOAEL) for t-BP to induce forestomach lesions in rats and mice is approximately 30 mg/kg. Systemic toxicity was not observed in either species with oral doses as high as 1112 mg/kg. Synonyms: Benzenecarboperoxoic acid; 1,1-dimethylester; Esperox 10; Trigonox C; t-BP.

Journal Article↗
PubMed1992

NTP technical report on the toxicity studies of para-Chloro-alpha,alpha,alpha Trifluorotoluene (CAS NO: 98-56-6) Administered in Corn Oil and alpha-Cyclodextrin to F344/N Rats and B6C3F1 Mice in 14-Day Comparative Gavage Studies.

p-Chloro-alpha,alpha,alpha trifluorotoluene (CTFT) is a volatile, aromatic liquid used as a chemical intermediate in the manufacture of dinitroaniline herbicides. To evaluate the toxicity of CTFT, groups of F344/N rats and B6C3F1 mice of each sex were administered CTFT by gavage once a day for 14 consecutive days in either corn oil or in an experimental molecular complex vehicle, a-cyclodextrin (alpha-CD). Dose levels selected for CTFT with the alpha-CD vehicle were 10, 50, and 400 mg/kg; dose levels used with the corn oil vehicle were 10, 50, 400, and 1000 mg/kg. The toxicokinetics of CTFT also were compared by gavage with the different vehicles and by i.v. administration. In genetic toxicity studies, CTFT was not mutagenic in Salmonella typhimurium. The elimination of an intravenous dose of CTFT from blood is best described by a triexponential equation. The data best fit a 3-compartment kinetic model with a very rapid distribution phase. A biexponential equation was found to best fit the elimination of CTFT from blood following a gavage dose in either corn oil or an aqueous molecular complex suspension, alpha-CD. However, the biological half-life (t 1/2) was the same in both routes, approximately 20 hours. Absorption of CTFT from the alpha-CD vehicle was found to be much faster than from corn oil. The average t 1/2 of the absorption phase for a 10 mg/kg dose of CTFT in the alpha-CD and corn oil vehicles was 7 and 150 minutes, respectively. Despite the differences in absorption, no statistical difference was observed in the calculated area under blood concentration versus time curves (AUC) obtained from rats dosed with CTFT in either vehicle. Blood concentrations of CTFT were proportional to dose, at levels as high as 400 mg/kg in both vehicles. The bioavailability of CTFT was shown to be complete in both vehicles, through comparing the AUC following oral and i.v. dosing. In 14-day toxicity studies, 1 of 10 female rats given the top dose of 1000 mg/kg CTFT in corn oil died on day 8; no deaths of male rats or of mice of either sex were attributable to the administration of CTFT. Body weight gains in all groups of rats and mice were similar with the exception of the top dose (1000 mg/kg) groups of male and female rats, which lost weight during the first week and resumed weight gain during the second. CTFT was found to accumulate in the kidneys of male rats, and there was a linear relationship between the kidney CTFT concentrations and the kidney levels of a2u-globulin, as determined by an ELISA assay. Microscopic changes in male rats included a dose-related toxic nephropathy consistent with that previously described as "hyaline droplet nephropathy." Dosed male and female rats also had hepatocyte hypertrophy and cytoplasmic vacuolization of the adrenal cortex. Clinical pathology findings suggested a mild anemia and cholestasis in rats. In contrast to rats, mice did not show appreciable CTFT concentrations in any tissue evaluated, suggesting a more rapid elimination of the chemical. However, hepatocellular hypertrophy, and clinical pathology findings consistent with cholestasis and mild liver injury, were noted in mice in the 400 and 1000 mg/kg dose groups. These studies demonstrated that oral doses of CTFT of 400 mg/kg or higher caused liver hypertrophy in rats and mice and adrenal changes in rats. Doses of 50 mg/kg or higher caused "hyaline droplet nephropathy" in male rats. The results were similar with CTFT administered either in corn oil or in alpha-CD (although absorption of CTFT was somewhat more rapid with alpha-CD), suggesting that alpha-CD may be an appropriate vehicle for toxicity studies with other chemicals. Synonyms: CTFT; p-Chloro-4-(trifluoromethyl) benzene; (p-chlorophenyl) trifluoromethane; 4-chlorobenzotrifluoride; Benzene, 1-chloro-4-(trifluoromethyl)-; p-(trifluoromethyl) chloro-benzene; p-chlorobenzotrifluoride; p-chlorotri-fluoromethylbenzene; p-trifluoromethylphenyl chloride; parachloro-alpha,alpha,alpha trifluorotoluene; parachlorobenzotrifluoride; parachlorotrifluoro-methylbenzene.

Journal Article↗
PubMed1992

NTP technical report on the toxicity studies of Trinitrofluorenone (Cas No. 129-79-3) Administered by Dermal Application and Dosed Feed to F344/N Rats and B6C3F1 Mice.

Trinitrofluorenone (TNF) is a major component of a toning formulation that at one time was used widely in certain photocopy processes. Because the principal route of exposure of humans to TNF probably would be dermal, studies were conducted to compare chemical absorption, distribution, excretion, and tissue retention, as well as toxicity in 14-day studies, by oral and dermal routes of exposure. Further, 13-week toxicity studies were carried out with TNF incorporated into the feed of rats and mice of both sexes. In genetic toxicity evaluations, TNF was found to be mutagenic in Salmonella typhimurium, with and without metabolic activation. In disposition and metabolism studies, excretion patterns following oral administration of radiolabeled TNF (in doses ranging between 1 and 100 mg/kg body weight) were similar; 20% and 70% of the administered dose appeared in urine and feces, respectively, during the first 72 hours. Residual radiolabel in tissues comprised less than 1% of the dose. The appearance in the feces of 60-70% of a 1 mg/kg i.v. dose provided evidence for substantial biliary excretion of TNF; studies of the radiolabeled materials extracted from urine and feces suggested that glucuronidation is a major biotransfomation of TNF and its metabolites. In the dermal exposure studies, groups of 5 F344/N rats and 5 B6C3F1 mice of each sex were administered TNF in acetone by topical application once a day, 5 days per week, for 14 days. Doses were 0, 7.5, 15, 30, 60, or 120 mg/kg body weight for rats and 0, 12.5, 25, 50, 100, or 200 mg/kg for mice. There were no deaths, no adverse clinical signs, and no gross or microscopic changes related to treatment in either species, except for discoloration of skin at the site of application. Disposition studies with female rats showed that less than 10% of a dermal dose of 47 mg and less than 3% of a dermal dose of 400 mg were available systemically. In contrast, toxicity was observed in the 14-day feeding studies with TNF. Groups of 5 rats and 5 mice of each sex were fed diets containing TNF at concentrations of 0, 500, 1600, 5000, 16000, or 50000 ppm. There were no deaths of rats or mice, but body weight gains of rats receiving 50000 ppm were reduced by as much as 45%. Animals receiving diets with 5000 ppm or higher TNF had a black discoloration of the skin and hair and enlarged and/or dark thyroid glands. Mild follicular cell hypertrophy and pigmentation of the epithelium and colloid were noted in the thyroid gland. Among mice, the brain and gallbladder were dark; the spleen of females was dark and also enlarged by hematopoiesis. Thymic lymphoid depletion and atrophy of the seminal vesicles were present in top-dose male rats (50000 ppm). In 13-week studies, groups of 10 animals of each sex received diets containing TNF at concentrations of 0, 1000, 2000, 4000, 8000, or 16000 ppm for rats, and 0, 3125, 6250, 12500, 25000, or 50000 ppm for mice. No rats died, but the deaths of several mice in the 50000 ppm groups indicated a possible relation to TNF ingestion. Body weight gains of dosed rats were lower than controls and were dose-related. Top-dose male mice gained markedly less weight than controls. A mild macrocytic anemia and increase in methemoglobin was present in dosed rats at the end of the study. In both species, there was a widespread occurrence of a dark brown pigment in dosed animals, with little evidence of toxicity related to the pigment accumulation. Other treatment- related effects in male rats included mesenteric vascular inflammation, renal inflammation, testicular degeneration with reduced sperm count and motility, splenic hematopoiesis, and oval cell hyperplasia, cytoplasmic alteration, and mixed cell foci in the liver. Top-dose female rats had centrilobular hepatocyte cytoplasmic alteration and splenic hematopoiesis. Dosed mice of both sexes showed cystic degeneration of the thyroid gland, liver hypertrophy, and splenic hematopoiesis. In summary, TNF caused a variety of lesions in oral feeding studies. The no-observed-adverse-effect-level (NOAEL) for microscopic ced-adverse-effect-level (NOAEL) for microscopic changes other than pigment accumulation was 1000 ppm for rats. A NOAEL could not be determined for mice from this study. Limited dermal absorption likely would prevent significant systemic toxicity resulting from contact of TNF with the skin. Synonyms: TNF; 2,4,7-trinitro-9H-fluoren-9-one.

Journal Article↗
PubMed1992

NTP technical report on the toxicity studies of Castor Oil (CAS No. 8001-79-4) in F344/N Rats and B6C3F1 Mice (Dosed Feed Studies).

Castor oil is a natural oil derived from the seeds of the castor bean, Ricinus communis. It is comprised largely of triglycerides with a high ricinolin content. Toxicity studies with castor oil were performed by incorporating the material at concentrations as high as 10% in diets given to F344/N rats and B6C3F1 mice of both sexes for 13 weeks. Genetic toxicity studies also were performed and were negative for mutation induction in Salmonella typhimurium, for induction of sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells, and for induction of micronuclei in the peripheral blood erythrocytes of mice evaluated at the end of the 13-week studies. Exposure to castor oil at dietary concentrations as high as 10% in 13-week studies did not affect survival or body weight gains of rats or mice (10 per sex and dose). There were no biologically significant effects noted in hematologic analyses in rats. Mild increases in total bile acids and in serum alkaline phosphatase were noted at various times during the studies in rats receiving the higher dietary concentrations of castor oil. Liver weights were increased in male rats receiving the 10% dietary concentration and in male and female mice receiving diets containing 5% or 10% castor oil. However, there were no histopathologic lesions associated with these liver changes, nor were there any compound-related morphologic changes in any organ in rats or mice. No significant changes were noted in a screening for male reproductive endpoints, including sperm count and motility, and no changes were observed in the length of estrous cycles of rats or mice given diets containing castor oil. Thus, no significant adverse effects of castor oil administration were noted in these studies. Synonyms: Ricinus Oil, oil of Palma Christi, tangantangan oil, phorboyl, Neoloid.

Journal Article↗
PubMed1992

NTP technical report on the toxicity studies of Toxicity Studies of Antimony Potassium Tartrate (CAS No. 28300-74-5) in F344/N Rats And B6C3F1 Mice (Drinking Water and Intraperitoneal Injection Studies).

Antimony potassium tartrate (APT) is a complex salt that until recently was used worldwide as an anti-schistosomal drug. APT was efficacious in humans only if administered intravenously at a near-lethal total dose of 36 mg/kg. Because unconfirmed epidemiologic studies suggested a possible association between APT treatment and bladder cancer, prechronic toxicity studies were initiated with APT to select a route of administration and appropriate doses in the event chronic studies were needed. To determine the most appropriate route for longer-term studies, toxicity and concentrations of tissue antimony were compared in F344/N rats and B6C3F1 mice that were administered APT in drinking water or by i.p. injection for 14 or 16 days. The animals were assigned to dose groups, 5/sex/species. Drinking water doses, estimated by water consumption, were 0, 16, 28, 59, 94, or 168 mg/kg in rats and 0, 59, 98, 174, 273, or 407 mg/kg in mice; i.p. doses were 0, 1.5, 3, 6, 11, or 22 mg/kg in rats and 0, 6, 13, 25, 50, or 100 mg/kg in mice. APT was poorly absorbed and relatively nontoxic when given orally. There was no mortality or histopathological lesions in rats or mice receiving doses of APT as high as 168 or 273 mg/kg, respectively. One mouse in the highest dose group (407 mg/kg) died, and there were treatment-related lesions in the liver and forestomach of most mice in this dose group. In contrast, i.p. administration of the drug was much more toxic, resulting in the deaths of rats administered 22 mg/kg; kidney and liver lesions were found in these rats. In mice, i.p. administration of APT caused deaths and liver lesions at dose levels one-fourth of those that caused similar effects by oral administration. All male and female mice injected with 100 mg/kg APT died; half of the female mice given 50 mg/kg APT died; additional deaths occurred with doses as low as 6 mg/kg. Hepatocellular necrosis and inflammation of the liver capsule were present in both sexes of mice in the 50 mg/kg dose groups. As a result of these findings, an i.p. dose regimen was selected for subsequent studies. Groups of ten male and female F344/N rats and B6C3F1 mice were given 0, 1.5, 3, 6, 12, or 24 mg/kg doses of APT 3 times per week for 13 weeks by i.p. injection. Rats were more sensitive than mice to the toxic effects of APT, exhibiting dose-related mortality and reduction in body weight. Four male rats in the 24 mg/kg dose died; body weights in both sexes of rats from this dose group and in male rats from the 12 mg/kg dose group were 10-20% below controls. No clinical signs of toxicity in the mice, nor gross or microscopic lesions, could be attributed to APT. Increased concentrations of antimony, considered to be dose-related, were detected in the blood, liver, kidney, spleen, and heart of rats, and in the liver and spleen of mice. In rats, hepatocellular degeneration and necrosis were associated with dose-related elevations in activities of the liver-specific serum enzymes, sorbitol dehydrogenase and alanine aminotransferase. By alternating the site of abdominal injection and the days of treatment, mesenteric inflammation at the site of administration was minimized in the rats and mice, indicating that the i.p. route would be suitable for chronic studies. Hepatotoxicity in rats occurred in dose groups where there was little evidence of renal toxicity and no cardiac toxicity; thus, serial measurement of liver-specific serum enzyme activities may be useful to monitor the presence and progression of hepatocellular degeneration in longer-term exposures. Synonyms: APT; Tartar emetic; tartrated antimony; tartarized antimony; potassium antimonyltartrate; Bis [μ-[2,3-dihydroxy- butanedioato(4-)-O1, O2:O3, O4]]-diantimonate dipotassium trihydrate (stereoisomer).

Journal Article↗
PubMed1992

NTP technical report on the toxicity studies of Ethylbenzene (Cas No. 100-41-4) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

Ethylbenzene is commonly used as a solvent and chemical intermediate and as an additive in some motor fuel formulations. Inhalation toxicology studies of ethylbenzene (99% pure) were conducted by exposing groups of F344/N rats and B6C3F1 mice of each sex to ethylbenzene vapor at chamber concentrations of 0, 100, 250, 500, 750, or 1000 ppm, 6 hours per day, 5 days per week for 13 weeks. No rats or mice died during the 13-week exposure. Body weight gains were slightly lower in the high dose groups of male and female rats, but the differences were not statistically significant. Absolute and relative kidney, liver, and lung weights were increased in the exposed rats, while weight increases occurred only in the livers of exposed mice. Chemically related histopathologic changes were not observed in any tissues of rats or mice. No changes were observed in the evaluation of sperm or vaginal cytology in rats or mice. Ethylbenzene was not mutagenic in Salmonella and did not induce chromosomal aberrations or sister chromatid exchanges in Chinese hamster ovary (CHO) cells in vitro, though it did induce trifluorothymidine resistance in mouse lymphoma cells at the highest concentration tested. Micronuclei assays in peripheral blood of mice were negative. Thus, there appears to be only minimal evidence of toxicity in F344/N rats and B6C3F1 mice exposed to ethylbenzene by inhalation at concentrations as high as to 1000 ppm for 13 weeks. Synonyms: EB, ethyl benzene, ethylbenzol, phenylethane. (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 Cresols (CAS Nos. 95-48-7, 108-39-4, 106-44-5) in F344/N Rats and B6C3F1 Mice (Feed Studies).

Cresols are monomethyl derivatives of phenol, and are found as constituents of coal tar, in various industrial solvents and resins, and in some essential oils. In 28-day toxicity studies, F344/N rats and B6C3F1 mice of both sexes were given o-cresol, m-cresol, p-cresol, or m/p-cresol (60:40) at concentrations from 300 ppm to 30,000 ppm in the diet. In 90-day studies, o-cresol or m/p-cresol (60:40) were added to the diet in concentrations as high as 30,000 ppm to F344/N rats and 20,000 ppm (o-cresol) or 10,000 ppm (m/p-cresol) to B6C3F1 mice. In the 28-day studies, all rats survived (5 per sex per dose), but some mice given o-cresol at 30,000 ppm, or m-cresol or p-cresol at 10,000 ppm or 30,000 ppm died before the end of the studies. Feed consumption was depressed during the first study week in all high- dose groups of animals and weight gains were generally less than controls in groups given 10,000 or 30,000 ppm in the four 28-day studies. Increased relative liver weights and kidney weights were noted in both rats and mice given concentrations of cresols as low as 3,000 ppm. However, there were no consistent microscopic changes associated with these weight increases. Bone marrow hypoplasia and uterus, ovary and occasional mammary gland atrophy were seen primarily at the highest dietary concentration, but also at 10,000 ppm with certain cresols. An effect specific to the p- cresol and m/p-cresol studies was atrophy and regenerative changes in the nasal epithelia and forestomach, presumably a direct result of the irritant effects of the chemical or its vapors. Results of reproductive tissue evaluations and estrus cycle characterizations with o-cresol and m/p-cresol gave no indication of adverse effects to the male reproductive system, but the estrus cycle was lengthened in rats and mice receiving the higher concentrations of o-cresol and rats receiving m/p-cresol. In the 90-day studies, no deaths of rats (20 per sex per dose) or mice (10 per sex and dose) could clearly be related to administration of either o-cresol or m/p-cresol. Hematology, clinical chemistry, and urinalysis results were generally unremarkable in all studies, although an accumulation of bile acids in high-dose rats was considered evidence of a deficit in hepatocellular function resulting from ingestion of the chemical. Results of microscopic analyses were consistent with findings in the 28-day studies, and revealed evidence of mild bone marrow hypocellularity in rats and forestomach hyperplasia in mice given diets containing the higher concentrations of o-cresol. Evidence of nasal irritation was present in rats and mice receiving feed containing m/p-cresol. Additional lesions in rats receiving m/p-cresol included bone marrow hypocellularity and uterine atrophy. The cresol isomers exhibited a generally similar pattern of toxicities in rats and mice. Dietary concentrations of 3,000 ppm appeared to be minimal effect levels for increases in liver and kidney weights and deficits in liver function. Histopathologic changes, including bone marrow hypocellularity, irritation to the gastrointestinal tract and nasal epithelia, and atrophy of female reproductive organs, occasionally occurred at 10,000 ppm, but were more common at the high-dose of 30,000 ppm. Synonyms: phenol, 2-methyl-(9CI); 2-cresol; o-cresylic acid; 1-hydroxy-2-methylbenzene; 2-hydroxytoluene; o-hydroxytoluene; 2-methylphenol; o-methylphenol; o-methylphenylol; o-oxytoluene; RCRA Waste Number U052; o-toluol; UN 2076; phenol, 3-methyl-(9CI); 3-cresol; m-cresole; m-cresylic acid; 1-hydroxy-3-methylbenzene; 3-hydroxytoluene; m-hydroxytoluene; m-kresol; 3-methylphenol; m-methylphenol; m-oxytoluene; RCRA Waste Number U052; m-toluol; UN 2076; phenol, 4-methyl- (9CI); 4-cresol; p-cresylic acid; 1-hydroxy-4-methylbenzene; 4-hydroxytoluene; p-hydroxytoluene; p-kresol; 1-methyl-4-hydroxybenzene; p-methylhydroxy- benzene; 4-methylphenol; p-methylphenol; p-oxytoluene; RCRA Waste Number U052; p-toluol; p-tolyl alcohol; UN 2076. (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 Tetrachlorophthalic Anhydride (CAS No. 117-08-8) Administered by Gavage to F344/N Rats and B6C3F1 Mice.

Tetrachlorophthalic anhydride (TCPA) is primarily used as a flame retardant in plastics. Toxicology studies were conducted by administering TCPA by oral gavage to F344/N rats and B6C3F1 mice for 13 weeks. Evaluations included histopathology, clinical pathology, and analyses of reproductive system parameters. The genetic toxicity of TCPA was assessed with in vitro tests of mutagenicity in Salmonella typhimurium and induction of sister chromatid exchanges and chromosomal aberrations in Chinese hamster ovary cells; sister chromatid exchanges and chromosomal aberrations were also determined in mouse bone marrow cells following in vivo exposure. The ability of TCPA to induce sex-linked recessive lethal mutations was also studied in vivo in Drosophila melanogaster. Groups of 10 rats and 10 mice of each sex received TCPA in corn oil vehicle by oral gavage (5 days/week) at doses of 0, 94, 187, 375, 750, and 1500 mg/kg. The deaths of 5 male rats and 1 female rat in the 1500 mg/kg dose group and 1 female rat in the 750 mg/kg dose group were considered due to chemical toxicity. Mean final body weights and body weight gains were depressed in male rats in the 375, 750, and 1500 mg/kg groups and in all groups of female rats receiving TCPA. Relative liver weights were slightly increased in males and females at doses of 187 mg/kg and higher, although a dose relationship was not apparent. Heart weights of surviving male rats in the high-dose group were also increased. Male and female rats exhibited dose-dependent increases in kidney weights and in the incidence and severity of renal tubule necrosis and/or dilation. No clinical pathology changes were clearly associated with chemical exposure. There were no chemical-related effects on survival, body weights, or organ weights in dosed mice. No chemical-related lesions were identified in organs examined microscopically. Decreases in red blood cell parameters consistent with a mild, poorly regenerative anemia were the only evidence of possible compound toxicity in dosed mice. Sperm morphology and vaginal cytology evaluations in rats and mice revealed no adverse changes related to TCPA exposure. In genetic toxicology studies, TCPA, tested with and without exogenous metabolic activation (S9), was not mutagenic in Salmonella typhimurium and did not induce sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells. In the Drosophila melanogaster sex-linked recessive lethal test, TCPA gave equivocal results when administered by feeding and negative results when administered by injection. No induction of chromosomal aberrations was observed in bone marrow cells of mice 17 hours after intraperitoneal injection of TCPA, although an increase in sister chromatid exchanges was detected in these cells 23 hours after injection. In summary, clear evidence of organ toxicity following administration of TCPA in corn oil by gavage for 13 weeks was limited to the kidney of rats. The no-observed-adverse-effect level for histopathologic lesions in this tissue was not achieved with doses as low as 94 mg/kg per day. No significant adverse effects were seen in mice given doses as high as 1500 mg/kg per day for 13 weeks. Synonyms: 4,5,6,7-Tetrachloro-1,3-isobenzofurandione; 1,3-dioxy- 4,5,6,7-tetrachloroisobenzofuran; 3,4,5,6-tetrachloro-1,2-benzene- dicarboxylic anhydride; niagathal; tetrathal.

Journal Article↗
PubMed1993

NTP technical report on the toxicity studies of Riddelliine (CAS No. 23246-96-0) Administered by Gavage to F344 Rats and B6C3F1 Mice.

Riddelliine is a naturally occurring pyrrolizidine alkaloid, a class of compounds occurring in rangeland plants of the genera Crotalaria, Amsinckia, and Senecio. Two-week and 13-week rodent toxicity studies of riddelliine were conducted because riddelliine can be a contaminant of foodstuffs, such as meat, grains, seeds, milk, herbal tea, and honey. In addition to histopathology, evaluations included clinical pathology and reproductive toxicity. In vitro genetic toxicity studies included assessments of mutagenicity in Salmonella typhimurium and of the induction of chromosomal aberrations and sister chromatid exchanges in Chinese hamster ovary cells. Riddelliine was also evaluated in vivo for the induction of micronuclei in mouse bone marrow and in peripheral blood and for the induction of S-phase synthesis and unscheduled DNA synthesis in the liver of rats and mice. In the 2-week studies, groups of five male and five female F344/N rats and B6C3F1 mice were administered riddelliine in 0.1 M phosphate buffer by gavage at dose levels of 0, 0. 33, 1.0, 3.3, 10, or 25 mg/kg body weight five times per week, for a total of 12 doses. Four of five male rats in the 25 mg/kg group died or were killed moribund before the end of the study. Mean body weight gains of male rats in the 10 and 25 mg/kg groups were depressed. No deaths or body weight effects were observed in female rats. Male rats had dose-related hemorrhagic centrilobular hepatic necrosis, hepatocytic karyomegaly and cytologic alterations, pulmonary hemorrhage and/or edema, splenic extramedullary hematopoiesis, and pancreatic edema. Female rats exhibited fewer and less severe lesions than identically treated male rats. Heart weights of treated male and female rats were lower than those of the controls. No deaths or effects on body weight were observed in treated mice. Dose-related increases in absolute and relative liver weights and increased incidences of hepatic cytomegaly were the only treatment-related findings in male and female mice administered riddelliine. In the 13-week studies, groups of 20 male and 20 female F344/N rats and B6C3FI mice were administered riddelliine in 0.1 M phosphate buffer by gavage five times per week for 13 weeks. Rats received 0, 0.1, 0.33, 1.0, 3.3, or 10 mg/kg and mice received 0, 0.33, 1.0, 3.3, 10, or 25 mg/kg. Ten animals from each dose group were killed after 13 weeks of treatment. The remaining 10 animals in each dose group were observed without further treatment for up to 14 weeks; five animals from each dose group were killed after 7 weeks of recovery, and the remaining five animals per dose group were killed at the end of the 14-week recovery period. During the 13-week treatment period, 19 of 20 male rats in the high-dose group died; all others survived. Body weight gains were decreased with increasing dose at Week 13. During the 14-week recovery period, all male rats survived, but five high-dose females died. Mean body weight gains of dosed and control male rats were similar throughout the 1 4-week recovery period; the final mean body weights of the treated males approached the final mean body weight of the controls. Similarly, mean body weight gains among the treated female rats were similar to the control value at the end of the 14- week recovery period. However, the final mean body weight of female rats given 1.0 or 3.3 mg/kg remained lower than that of controls at the end of the 14-week recovery period. In the 13-week study, the most significant treatment-related histopathologic lesions in rats occurred in the liver and included hepatocyte cytomegaly and karyomegaly, cytoplasmic vacuolization, centrilobular necrosis, mixed inflammatory cell infiltration, and bile duct hyperplasia. Vascular lesions in the kidneys and lungs were observed in most high- dose rats after 13 weeks of riddelliine administration. Additional lesions were found in the heart, spleen, kidneys, and pancreas at 13 weeks. At the end of the 14-week recovery period, hepatocyte karyomegaly, cytomegaly, and cytoplasmic vacuolization persisted. In addition, the incidence of bile duct hyperplasia was markedly increased in dosed female rats, and foci of cytologic alteration or hyperplastic hepatocytes were observed in dosed rats that were allowed to recover for up to 14 weeks. Adenomas of the liver occurred in 2 of 10 females in the 10 mg/kg group at 13 weeks and in one of five females in this group after the 14-week recovery period; no adenomas were found in the livers of control females. Serum activities of alkaline phosphatase in male rats and sorbitol dehydrogenase in female rats increased with increasing dose. Reticulocyte counts consistently increased and platelet counts consistently decreased with increasing dose in treated male and female rats. The clinical pathology findings were indicative of liver damage and erythrocyte and platelet sequestration. In mice in the 13-week study, no deaths related to riddelliine treatment occurred. Body weight gains were depressed at the two highest dose levels (10 and 25 mg/kg); the depression in body weight persisted throughout the 14- week recovery period. Dose-related increases in erythrocyte counts in male mice and in reticulocyte counts in female mice were observed. Dose-related decreases in platelet counts were also observed in both males and females. Centrilobular cytomegaly in the liver was noted at 13 weeks in males and females administered 25 mg/kg riddelliine; this lesion persisted through the recovery period in females. At the end of the 14-week recovery period, bile duct hyperplasia was seen in the liver in high-dose female mice. Epithelial hyperplasia of the forestomach was noted in male and female mice in the 10 and 25 mg/kg groups after 13 weeks of treatment, but this lesion became less severe during the recovery period. In male rats administered up to 3.3 mg/kg and in male mice administered up to 25 mg/kg for 13 weeks, riddelliine did not adversely affect any of the reproductive end points evaluated. In female rats given 10 mg/kg and in female mice given 25 mg/kg, the length of the estrous cycle was increased. However, no unequivocal adverse effects were noted on fertility, pup growth and survival, or weight gain of dams during pregnancy during the mating trial in rats, although mean body weights of dams given 0.1 or 1.0 mg/kg were significantly lower than the mean body weight of the controls throughout gestation and lactation. In contrast, riddelliine administered at a dose of 25 mg/kg was toxic to the dams in the mouse mating trial, resulting in lower body weights at the beginning of gestation and throughout lactation. Administration of 25 mg/kg riddelliine to mouse dams also affected fetal growth and survival; the average live litter size was significantly reduced, the number of pups born dead was increased, and the average pup weight was reduced throughout the 21-day postpartum period. Riddelliine was mutagenic in Salmonella typhimurium strain TA100 with, but not without, S9 activation; results of mutagenicity testing were negative in strains TA97, TA98, and TA1535. Riddelliine induced sister chromatid exchanges in Chinese hamster ovary (CHO) cells with and without S9. Chromosomal aberrations were induced in CHO cells only in the presence of S9. The frequency of micronucleated erythrocytes in mouse peripheral blood samples was not elevated after 4 or 13 weeks of daily gavage treatments; however, a weakly positive response was noted in the peripheral blood and bone marrow of male mice administered a single, high dose of riddelliine by gavage. Unscheduled DNA synthesis was detected in cultured hepatocytes from male and female rats and mice following 5 or 30 days of riddelliine treatment by gavage. In addition, an increase in S-phase DNA synthesis was observed in cultured hepatocytes of male and female rats treated for either time period. In summary, the administration of riddelliine to rodents by gavage for up to 13 weeks resulted in a spectrum of neoplastic and nonneoplastic effects similar to those previously described for other pyrrolizidine alkaloids. Rats were found to be somewhat more sensitive than mice, and males more sensitive than females, to the toxic effects of riddelliine. The no-observed-adverse-effect level (NOAEL) for histopathologic changes in the 13-week studies was 3.3 mg/kg body weight for mice and 0.1 mg/kg body weight for rats. The liver was the primary target of riddelliine-induced injury that resulted in lesions characterized by cytomegaly and cytologic alteration in rats and mice and also by marked necrotic and proliferative changes in rats. Riddelliine is carcinogenic to female F344/N rats, based on the occurrence of hepatocellular adenomas. Synonyms: 13,19-didehydro-12,18-dihydroxy senecionan-11,16- dione; trans-15-ethylidine-12b-hydroxy-12a-hydroxymethyl-13-methylenesenec-1-enine; 3-ethylidine-3,4,5,6,9,11,13,14,14a,14b-decahydro-6-hydroxy-6-(hydroxymethyl)-5-methylene (1,6)di-oxacyclododecino(2,3,4-gh)-pyrrolizidine-2,7-dione.

Journal Article↗
PubMed1993

NTP technical report on the toxicity studies of Ethylene Glycol Ethers: 2-Methoxyethanol, 2-Ethoxyethanol, 2-Butoxyethanol (CAS Nos. 109-86-4, 110-80-5, 111-76-2) Administered in Drinking Water to F344/N Rats and B6C3F1 Mice.

Glycol alkyl ethers represent a class of high-production-volume chemicals with widespread industrial applications as solvents and chemical intermediates. Comparative toxicity studies with three glycol ethers, 2-methoxyethanol, 2-ethoxyethanol, and 2-butoxyethanol, were conducted in F344/N rats and B6C3F1 mice in both 2-week and 13-week drinking water studies. Toxicologic endpoints evaluated in animals included histopathology, hematology, clinical chemistry, urinalysis, and reproductive system parameters. Genetic toxicity was also evaluated for each glycol ether in several in vitro and in vivo assays. In the 2-week studies, groups of five male and five female rats and mice received 2-methoxyethanol, 2-ethoxyethanol, or 2-butoxyethanol in the drinking water. Estimates of compound consumption based on water consumption by male and female rats ranged from 100 to 400 mg/kg for 2-methoxyethanol, 200 to 1600 mg/kg for 2-ethoxyethanol, and 70 to 300 mg/kg for 2-butoxyethanol. For mice, consumption values ranged from 200 to 1300 mg/kg for 2-methoxyethanol, 400 to 2800 mg/kg for 2-ethoxyethanol, and 90 to 1400 mg/kg for 2-butoxyethanol. There were no chemical-related effects on survival for rats or mice in the 2-week studies. Decreased body weight gains were noted for both male and female rats treated with 2-methoxyethanol or 2-ethoxyethanol for 2 weeks, and there were dose-related decreases in water consumption for rats of each sex treated with the ethylene glycol ethers. Most of the changes in organ weights for rats and mice treated with the glycol ethers were sporadic (mice) or related to low final mean body weights (rats), except for thymic atrophy in male and female rats and testicular atrophy in males of both species receiving 2-methoxyethanol or 2-ethoxyethanol. In the 13-week studies in rats, groups of 10 males and 10 females received 2-methoxyethanol, 2-ethoxyethanol, or 2-butoxyethanol in the drinking water at concentrations ranging from 750 to 6000 ppm, 1250 to 20,000 ppm, or 750 to 6000 ppm, respectively. In the 13-week studies in mice, groups of 10 males and 10 females received 2-methoxyethanol, 2-ethoxyethanol, or 2-butoxyethanol in the drinking water at concentrations ranging from 2000 to 10,000 ppm, 2500 to 40,000 ppm, or 750 to 6000 ppm, respectively. Estimates of compound consumption based on water consumption by male and female rats ranged from 70 to 800 mg/kg for 2-methoxyethanol, 100 to 2200- mg/kg for 2-ethoxyethanol, and 70 to 500 mg/kg for 2-butoxyethanol. For-mice, consumption values ranged from 300 to 1800 mg/kg for 2-methoxyethanol, 600 to 11,000 mg/kg for 2-ethoxyethanol, and 100 to 1300 mg/kg for 2-butoxyethanol. Chemical-related mortality occurred in male and female rats administered 4500 or 6000 ppm 2-methoxyethanol and in male and female rats administered 20,000 ppm 2-ethoxyethanol. No deaths occurred in rats administered 2-butoxyethanol or in mice administered 2-methoxyethanol, 2-ethoxyethanol, or 2-butoxyethanol. Decreased body weight gains occurred in dosed rats and mice in all three studies; the greatest reductions in body weight gain were seen with 2-methoxyethanol. In rats administered 2-methoxyethanol or 2-ethoxyethanol, treatment-related histopathologic changes were observed in the testes, thymus, and hematopoietic tissues (spleen, bone marrow, and liver). A dose-related degeneration of the germinal epithelium in the seminiferous tubules of the testes was more severe in 2-methoxyethanol-treated rats than in rats treated with 2-ethoxyethanol. In special stop-exposure studies in male rats in which administration of the glycol ethers was stopped after 60 days, marked degeneration of the seminiferous tubules was present in rats treated with 3000 ppm 2-methoxyethanol, and mild to moderate degeneration was observed in rats treated with 1500 ppm. Moderate to marked testicular degeneration was present in rats treated with 10,000 or 20,000 ppm 2-ethoxyethanol but not in rats treated with 5000 ppm. After 30 and 56 days of recovery from treatment with these chemicals, only partial recovery from testicular degeneration was observed. There was no testicular degeneration after 60 days of treatment with 1500 to 6000 ppm 2-butoxyethanol. 2-Methoxyethanol treatment for 13 weeks resulted in a progressive anemia associated with a cellular depletion of bone marrow and fibrosis of the splenic capsule. Anemia was also seen with 2-ethoxyethanol, but evidence of an adaptive response was indicated by increased hematopoiesis in the bone marrow, spleen, and liver. Toxicity with 2-butoxyethanol was limited to the liver and hematopoietic system. Cytoplasmic alteration and a minimal hepatocellular degeneration were present in the liver of male and female rats. A minimal anemia was present, and a hematopoietic response was evident in the bone marrow and spleen. In mice, 2-methoxyethanol and 2-ethoxyethanol had similar effects on the testes, spleen, and adrenal gland (females only). A dose-related degeneration of the germinal epithelium in seminiferous tubules of the testes was more severe with 2-methoxyethanol than with 2-ethoxyethanol. A dose-related increase in splenic hematopoiesis was also more prominent with 2-methoxyethanol. Both 2-methoxyethanol and 2-ethoxyethanol caused a prominent lipid vacuolization of the X-zone of the adrenal gland in female mice. There were no chemical-related lesions attributed to 2-butoxyethanol administration in mice. All three of the glycol ethers were negative in Salmonella typhimurium mutation tests conducted with and without induced hamster and rat liver S9. In the mouse lymphoma L5178Y cell mutation assay, 2-ethoxyethanol was negative without S9 but was weakly positive in the presence of induced rat liver S9; 2-methoxyethanol and 2-butoxyethanol were not tested in this assay. At high concentrations, 2-ethoxyethanol induced sister chromatid exchanges (SCEs) in Chinese hamster ovary cells with and without S9. Chromosomal aberrations (Abs) were also induced by 2-ethoxyethanol, but only in the absence of S9 and without a delay in cell cycle. In contrast, 2-butoxyethanol induced cell cycle delay but did not induce SCEs or Abs with or without S9. 2-Ethoxyethanol was the only glycol ether tested for induction of sex-linked recessive lethal mutations in germ cells of Drosophila melanogaster; both feeding and injection trials were negative. In summary, based on survival, decreased body weight gains, and histopathologic effects, the rank order of toxicity for the three glycol alkyl ethers was 2-methoxyethanol>2-ethoxyethanol>2-butoxyethanol; the toxic effects were more severe in rats than in mice. In the 13-week study of 2-methoxyethanol in rats, a no-observed-adverse-effect level (NOAEL) was not reached, since testicular degeneration in males and decreased thymus weights in males and females occurred at the lowest concentration administered (750 ppm). In the 13-week study of 2-ethoxyethanol in rats, the NOAEL for decreased thymus weights in males was 1250 ppm; for female rats treated with 2-ethoxyethanol for 13 weeks, the NOAEL for all histopathologic and hematologic effects was 5000 ppm. In rats treated with 2-butoxyethanol for 13 weeks, the NOAEL for liver degeneration was 1500 ppm in males and females. For male mice treated with 2-methoxyethanol for 13 weeks, the NOAEL for testicular degeneration and increased hematopoiesis in the spleen was 2000 ppm. A NOAEL was not reached for female mice treated with 2-methoxyethanol, since adrenal gland hypertrophy and increased hematopoiesis in the spleen occurred at the lowest concentration administered (2000 ppm). For male mice treated with 2-ethoxyethanol for 13 weeks, the NOAEL for testicular degeneration and increased hematopoiesis in the spleen was 20,000 ppm. For female mice in the 13-week study of 2-ethoxyethanol, the NOAEL for adrenal gland hypertrophy and increased hematopoiesis in the spleen was 5000 ppm. No clear chemical-related effects were seen in male or female mice administered 2-butoxyethanol for 13 weeks at concentrations as high as 6000 ppm. Synonyms: 2-Methoxyethanol: Ethylene glycol monomethyl ether; methyl cellosolve; 2-Ethoxyethanol: Ethylene glycol monoethyl ether; cellosolve; 2-Butoxyethanol: Ethylene glycol monobutyl ether; butyl cellosolve.

Journal Article↗
PubMed1993

NTP technical report on the toxicity studies of Glutaraldehyde (CAS No. 111-30-8) Adminstered by Inhalation to F344/N Rats and B6C3F1 Mice.

Glutaraldehyde is a potent sensory irritant with the capability to cross-link, or fix, proteins. It is used industrially as an antimicrobial agent and as a cold sterilant in hospitals, and it has a variety of other industrial uses. The toxicity of glutaraldehyde was evaluated in 2-week and 13-week inhalation exposure studies in F344/N rats and B6C3F1 mice. In addition to histopathology, evaluations included clinical pathology and assessments of sperm morphology and estrous cycle length. In vitro genetic toxicity studies 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. The ability of glutaraldehyde to induce sex-linked recessive lethal mutations was also studied in vivo in Drosophila melanogaster. In 2-week inhalation studies, groups of five rats and five mice of each sex were exposed to glutaraldehyde by whole-body inhalation at concentrations of 0, 0.16, 0.5, 1.6, 5, and 16 ppm for 6 hours per day, 5 days per week. All rats and mice exposed to 5 or 16 ppm glutaraldehyde died before the end of the studies; all mice exposed to 1.6 ppm also died. Rats exposed to 1.6 ppm did not gain weight. Deaths were attributed to severe respiratory distress. Mice appeared to be more sensitive than rats because the small airways of the nasal passage of mice were more easily blocked by cell debris and keratin. Lesions noted in the nasal passage and larynx of rats and mice included necrosis, inflammation, and squamous metaplasia. At higher exposure concentrations, similar lesions were present in the trachea of rats and mice and in the lung and on the tongue of rats. In 13-week studies, groups of 10 rats and 10 mice of each sex were exposed to glutaraldehyde by whole-body inhalation at concentrations of 0, 62.5, 125, 250, 500, and 1000 ppb for 6 hours per day, 5 days per week. There were no exposure-related deaths in rats, but all mice exposed to 1000 ppb and two female mice exposed to 500 ppb died before the end of the study. Body weight gains were reduced in male rats exposed to 1000 ppb and in female rats exposed to 500 or 1000 ppb. Body weight gains of male mice exposed to 125, 250, or 500 ppb and female mice exposed to 250 or 500 ppb were reduced in a concentration-related manner. There was no clear evidence of systemic toxicity in rats or mice by histopathologic or clinical pathology assessments; however, exposure-related lesions in the respiratory tract were observed, and resembled those noted in the 2-week studies. In rats, the most severe lesions occurred in the anterior portions of the nasal passages and involved both the respiratory and olfactory epithelium. Hyperplasia and squamous metaplasia were most commonly noted on the lateral wall of the nasal cavity and on the tips of the nasoturbinates. Lesions were most extensive in rats exposed to 1000 ppb, but were also noted in the 250 and 500 ppb groups and in one male exposed to 125 ppb. In mice, histopathologic lesions in the respiratory tract were most severe in animals in the 1000 ppb group and consisted of minimal to mild squamous metaplasia of the laryngeal epithelium, suppurative inflammation in the anterior parts of the nasal cavity, and minimal squamous metaplasia on the tips of the nasoturbinates. Necrosis and inflammation were noted at lower concentrations, primarily in the anterior portion of the nasal passage. In genetic toxicity studies, glutaraldehyde was mutagenic with and without S9 metabolic activation in Salmonella typhimurium strains TA100, TA102, and TA104. Glutaraldehyde was mutagenic in mouse L5178Y lymphoma cells in the absence of S9 and induced sister chromatid exchanges in Chinese hamster ovary cells with and without S9. In one laboratory, chromosomal aberrations were induced in Chinese hamster ovary cells by glutaraldehyde in the absence of S9 only; no increase in chromosomal aberrations was observed with or without S9 in a second laboratory. Glutaraldehyde did not induce sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster treated as adults by feeding or injection or treated as larvae by feeding. In summary, exposure of rats and mice to glutaraldehyde by inhalation for up to 13 weeks resulted in a spectrum of necrotic, inflammatory, and regenerative lesions confined to the upper respiratory tract. Mice were somewhat more sensitive than rats because the small airways of the nasal passage in mice were more prone to blockage with cellular debris, bacteria, and keratin. The no-observed-adverse-effect level (NOAEL) was 125 ppb for respiratory lesions in rats. An NOAEL was not reached for mice, as inflammation was found in the anterior nasal passage at concentrations as low as 62.5 ppb. Synonyms: 1,5-Pentanedial; glutaral; glutaric dialdehyde; 1,3-diformylpropane.

Journal Article↗
PubMed1993

NTP technical report on the toxicity studies of 1,6-Hexanediamine Dihydrochloride (CAS No. 6055-52-3) Administered by Drinking Water and Inhalation to F344/N Rats and B6C3F1 Mice.

1,6-Hexanediamine (HDA) is an aliphatic amine that is produced in large volumes in the United States. HDA is widely used as a corrosion inhibitor in lubricants and as an intermediate in the industrial synthesis of paints, resins, inks, and textiles. Toxicity studies of the dihydrochloride salt of HDA (HDDC) were conducted in male and female Fischer 344/N rats and B6C3F1 mice by the drinking water (2-week studies only) and whole-body inhalation routes (2-week and 13-week studies). Animals were evaluated for histopathology, clinical chemistry, hematology, and reproductive toxicity. In addition, the genetic toxicity of HDA was assessed in Salmonella typhimurium and in Chinese hamster ovary cells in vitro; HDDC was evaluated in the mouse micronucleus assay in vivo. In the 2-week drinking water studies, groups of 5 rats of each sex received HDDC at doses of 0.75 to 6.7 mg/mL, and groups of 5 mice of each sex received doses of 0.2 to 3.0 mg/mL for 14 or 15 days. All animals survived to the end of the studies. No gross or microscopic pathologic changes and no clinical abnormalities related to HDDC consumption were seen in any dose group. The only statistically significant change was a slight decrease in absolute and/or relative liver weights of female rats in the 1.7, 5.0, and 6.7-mg/mL treatment groups, in male rats in the 3.0 mg/mL treatment group, and in female mice in the 0.8 mg/mL treatment group. Because there was no significant toxicity in these studies, 13-week drinking water studies were not conducted. In the 2-week inhalation studies, 5 rats and 5 mice of each sex were exposed to 0, 10, 30, 89, 267, or 800 mg HDDC/m(3) for 6-hours per day for 12 days. In the highest exposure group (800 mg/m(3)), all male and female rats, all female mice, and 2 male mice died before the end of the studies. In the remaining groups, there was a dose-dependent depression in body weight gain in male and female mice, but not in rats. Clinical signs were primarily related to upper respiratory tract irritation and included dyspnea and nasal discharge in rats and mice. Absolute and relative liver weights were reduced in some male mice, but this did not occur in a dose- dependent manner. In rats, histopathologic lesions that were considered related to chemical exposure included inflammation and necrosis of laryngeal epithelium as well as focal inflammation and ulceration of the respiratory and olfactory nasal mucosa. In mice, focal areas of inflammation and necrosis were present in the respiratory mucosa of the larynx and trachea in the 2 highest exposure groups. Nasal lesions, including focal inflammation and ulceration, and degeneration and necrosis of the olfactory and respiratory epithelium were also seen in mice. In addition, mild testicular degeneration was present in 2 mice from the highest exposure group (800 mg/m(3)). In the 13-week inhalation studies, 10 rats and 10 mice of each sex were exposed to 0, 1.6, 5, 16, 50, or 160 mg HDDC/m(3) for 6 hours per day, 5 days per week for 13 weeks. In addition special groups of 20 male and 40 female rats and mice (mating trial animals) at each exposure level were included to assess the effect of HDDC on reproduction. All rats and mice in the base-study groups survived to the end of the studies, and there were no exposure-related changes in body weight. In the mating trials, 3 female mice exposed to 16 mg/m(3) and 1 female and 1 male mouse exposed to 50 mg/m(3) died before scheduled termination. These deaths, however, were not considered to be chemical related. In male mice in the base study, liver weights were increased relative to controls in the 2-highest exposure groups. No exposure-related changes in absolute or relative organ weights and no exposure-related clinical signs or gross lesions were seen in either species. In female rats, a dose-related decrease in white blood cell count was observed. Chemical-related microscopic lesions in male and female rats and mice were limited to the upper respiratory tract (larynx and nasal passages) in the 2 highest exposure groups and were similar in both species. These lesions included minimal to mild focal erosion/ulceration, inflammation, and hyperplasia of the laryngeal epithelium as well as degeneration of the olfactory and respiratory nasal epithelium. HDDC caused no significant changes in sperm morphology or in the length of the estrous cycle of rats or mice. In mating trials, HDDC demonstrated no adverse effects on reproduction of rats. The only statistically significant changes in reproductive parameters of mice were a slight increase in gestation length in the 50 mg/m(3) and 160 mg/m(3) exposure groups and a decrease in mean pup weight on Day 21 in the highest exposure group. These changes were not considered to be biologically significant. 1,6-Hexanediamine was not mutagenic in 4 strains of Salmonella typhimurium, and it did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells. These in vitro tests were conducted with and without exogenous metabolic activation (S9). Negative results were also obtained in an in vivo test that measured the frequency of micronucleated erythrocytes in peripheral blood of male and female mice. In summary, the toxicity of HDDC to rats and mice resulted from irritant properties of the chemical and was consistent with the effects of other irritant chemicals administered by inhalation. This toxicity was limited to the nose and airways. In the 2-week inhalation studies, deaths occurred in both rats and mice at the highest exposure level (800 mg/m(3)). In the 13-week studies, the no-observed-adverse-effect-level (NOAEL) for respiratory damage was 5 mg/m(3) for rats and mice. HDDC had no adverse effect on reproduction of either species and was not genotoxic. Synonyms: Hexamethylenediamine dihydrochloride; 1,6-diaminohexane dihydrochloride; 1,6-hexamethylenediamine dihydrochloride; 1,6- hexylenediamine dihydrochloride; 1,6-diamino-n-hexane dihydrochloride; HMDA; HDA; HDDC.

Journal Article↗
PubMed1992

NTP Technical report on the toxicity studies of ortho-, meta-, and para- Nitrotoluenes (CAS Nos. 88-72-2, 99-08-1, 99-99-0) Administered in Dosed Feed to F344/N Rats And B6C3F1 Mice.

Nitrotoluenes are high production volume chemicals used in the synthesis of agricultural and rubber chemicals and in various dyes. Because of differences in the metabolism of the 3 isomers and their capability to bind to DNA, comparative toxicity studies of o-, m-, or p-nitrotoluene were conducted in F344 rats and B6C3F1 mice. Animals were evaluated for histopathology, clinical pathology, and toxicity to the reproductive system. The nitrotoluenes were also studied in several in vitro and in vivo assays for genetic toxicity. In 14-day studies, o-nitrotoluene, m-nitrotoluene, or p-nitrotoluene was administered in the feed to male and female rats and mice at concentrations ranging from 388 to 20000 ppm (5 animals/chemical/species/sex/dose). There were no effects on survival or clinical signs of toxicity in these studies, although animals at the higher doses showed decreases in body weight gains relative to controls. In the 13-week studies, o-, m-, or p-nitrotoluene was given to male and female rats and mice (10 animals/chemical/species/ sex/dose) in the feed at concentrations between 625 and 10000 ppm. The estimated daily doses based on measures of feed consumption were 40 to 900 mg nitrotoluene/kg body weight/day for rats and 100 to 2000 mg/kg/day for mice and were similar for each of the 3 isomers when compared for each dietary level/sex/species. There were no effects on survival in any of the studies, and clinical signs of toxicity were limited to decreases in feed consumption. Decreased body weight gains occurred in dosed rats and mice in all studies at the higher dose levels and were most pronounced in rats receiving o-nitrotoluene. In rats, histopathologic analyses after 13 weeks of dosing showed toxicity to kidney, spleen, and testis in animals receiving any of the 3 isomers, and toxicity to the liver and mesothelium in male rats given o-nitrotoluene. Kidney toxicity observed in male rats was characterized by the presence of hyaline droplets in tubular epithelial cells, attributed to an increase in the level of alpha-2μ-globulin. Pigment, possibly lipofuscin, and karyomegaly in the p-nitrotoluene study were present in the renal tubular epithelium of dosed male and female rats. In the spleen of treated male and female rats, there was a mild increase in hematopoiesis, hemosiderin deposition, and/or congestion; this effect was most severe with the para-isomer, followed by the ortho- and then the meta-isomer. Administration of o-, m-, or p-nitrotoluene impaired testicular function of the rat, shown by degeneration of the testis and reduction in sperm concentration, motility, and spermatid number. All 3 isomers increased the length of the estrous cycle in rats. Hepatic toxicity was characterized by cytoplasmic vacuolization and oval cell hyperplasia and by an increase in the level of serum bile acids, SDH, and ALT activities in male rats given o-nitrotoluene. There was no histopathologic evidence for liver toxicity in male or female rats with the m- or p-isomers, or in female rats with the o-isomer; but evidence of liver injury was observed in these groups, indicated by increases in relative liver weights and elevations in bile acids and liver enzymes in serum. Mesotheliomas of the tunica vaginalis were observed in 3/10 male rats receiving o-nitrotoluene at 5000 ppm, and mesothelial cell hyperplasia was observed in 2/10 male rats receiving o-nitrotoluene at 10000 ppm. The only histopathologic evidence for toxicity in mice in the 13- week studies occurred in the olfactory epithelium in mice receiving o-nitrotoluene, where the chemical caused degeneration and metaplasia. No liver lesions were noted in mice, but the 3 isomers caused increases in relative liver weights. There was no toxicity to the reproductive system in male or female mice treated with any of the nitrotoluene isomers. The 3 nitrotoluene isomers were not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, and TA98. Only p-nitrotoluene induced chromosomal aberrations in cultured Chinese hamster ovary (CHO) cells, and this required metabolic activation. Sister-chromatid exchanges were increased in CHO cells following exposure to each isomer; the requirement for metabolic activation varied. Only p-nitrotoluene was studied in the mouse lymphoma L5178Y test; it caused mutations with metabolic activation. Unscheduled DNA synthesis (UDS) was increased in in vitro incubations of hepatocytes isolated from both sexes of rats and mice after receiving a single in vivo oral dose of o-nitrotoluene. UDS was not increased in a similar study with male rats given m- or p-nitrotoluene. o-Nitrotoluene also induced s-phase DNA synthesis in hepatocytes of rats but not in those of mice. In summary, the 3 nitrotoluene isomers were toxic to the kidney, spleen and/or reproductive system in rats; o-nitrotoluene also caused lesions in the liver of male rats. No treatment-related lesions were noted in mice except with o-nitrotoluene where olfactory epithelium degeneration occurred. The increase in relative liver weights and the increase in UDS in liver indicate that all 3 isomers affected the liver of female rats and of male and female mice, even though histopathologic lesions were not observed. In general, the extent of the toxicity was most severe with the o-isomer in both rats and mice. o-Nitrotoluene was carcinogenic in male rats in 13-week studies, based on the occurrence of mesothelioma and mesothelial cell hyperplasia in dosed groups. Synonyms: o-NT, 2NT, 2-nitrotoluene, 2-methylnitrobenzene, 2-nitrotoluol; m-NT, 3NT, 3-nitrotoluene, 3-methylnitrobenzene, 3-nitrotoluol; p-NT, 4NT, 4-nitrotoluene, 4-methylnitrobenzene, 4-nitrotoluol.

Journal Article↗
PubMed1992

NTP technical report on the toxicity studies of N,N-Dimethylformamide (CAS No. 68-12-2) Administered by Inhalation to F344/N Rats and B6C3F1 Mice.

N,N-Dimethylformamide (DMF), a colorless liquid with a high boiling point, is a solvent used in a large number of industrial processes. Male and female F344/N rats (30/sex/group) and B6C3F1 mice (10/sex/group) were exposed to DMF vapors at concentrations of 0, 50, 100, 200, 400, or 800 ppm, 6 hours/day, 5 days/week, for 13 weeks in whole body exposure inhalation studies. In addition to histopathology, sperm morphology, and vaginal cytology, which were evaluated in both species, the studies examined clinical pathology, cardiovascular, and renal function in rats only. In genetic toxicity studies, DMF was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, or TA98, with or without S9 activation, nor did it induce germ cell mutations in male Drosophila melanogaster treated by feeding or injection. No induction of sister chromatid exchanges or chromosomal aberrations was noted in cultured Chinese hamster ovary cells treated in vitro with DMF, with or without an S9 metabolic activation system. In one laboratory, a marginal increase in mutant colonies was observed after treatment of mouse lymphoma L5178Y/TK+/- cells with DMF in the absence of S9; results from studies in 2 other laboratories were negative. In the 13-week studies, all rats survived exposures to DMF. Body weight gains were reduced by 50-65% in rats exposed at 800 ppm and to a lesser extent in the 400 ppm group. Evidence of hepatocellular injury was noted as early as day 4, based on increases in activities of liver-specific enzymes in serum in rats of both sexes exposed at 200-800 ppm. Serum cholesterol levels were increased at all exposure concentrations. Relative liver weights were increased in male rats exposed at 100 ppm and higher concentrations, and in female rats at all concentrations. Minimal to moderate centrilobular hepatocellular necrosis was seen in rats of both sexes exposed at 400 and 800 ppm; the lesion was more severe in females. There were no clear, adverse effects seen in urinalyses, in electrocardiographic studies, or in male reproductive system evaluations that could be related to DMF exposure. Hematologic studies showed mild hemoconcentration in males and females. Prolonged diestrus was observed in females exposed at 800 ppm. Among mice exposed to DMF for 13 weeks, there was no chemically related mortality. Body weight gains were approximately 30% less than controls in females exposed at 800 ppm. Relative liver weights were increased in males and females at all exposure concentrations. Centrilobular hepatocellular hypertrophy (minimal to mild) was found in all groups of male mice exposed to DMF, and in female mice exposed at 100 ppm and higher concentrations. The length of the estrous cycle in mice increased with increasing DMF exposure. In summary, DMF-related effects were seen in the liver of both rats and mice, with rats being more severely affected. For rats of both sexes, the no-observed-adverse-effect level (NOAEL) was 200 ppm, based on the absence of liver histopathology, although liver function assays and liver weights showed changes at all exposure levels (as low as 50 ppm). For mice, hepatocellular hypertrophy or increased liver weights occurred at all exposure concentrations. Synonyms: DMF, DMFA.

Journal Article↗
PubMed1992

NTP technical report on the toxicity studies of 2-Hydroxy-4-methoxybenzophenone (CAS No. 131-57-7) Adminstered Topically and in Dosed Feed to F344/N Rats and B6C3F1 Mice.

2-Hydroxy-4-methoxybenzophenone (HMB) occurs naturally in flower pigments and is synthesized for use in sunscreens, as a UV stabilizer in various cosmetic products, and in plastic surface coatings and polymers. Toxicity studies of HMB were performed in F344/N rats and B6C3F1 mice, by administering HMB in feed and by topical application, in studies of 2 weeks' (5 animals/sex, dose and species) and 13 weeks' (10 animals/sex, dose and species) duration. Assessments included hematology, clinical chemistry, urinalysis, reproductive toxicity, and histopathologic evaluations. In both 2- and 13-week dosed feed studies, rats received diets containing 0, 3125, 6250, 12500, 25000, or 50000 ppm HMB. One high-dose female rat died during the 2-week study. Body weight gains of high-dose male and female rats were reduced in the 13-week study. Liver and kidney weights were increased in dosed rats in both studies. In the 2-week studies, enlarged livers were associated with a marked hepatocyte cytoplasmic vacuolization in rats receiving diets containing concentrations of 6250 ppm HMB or higher; renal lesions, consisting of dilated tubules and regeneration of tubular epithelial cells, were found primarily in high-dose rats. In the 13-week studies, kidney lesions progressed to include papillary degeneration, or necrosis, and inflammation, while the liver lesion appeared to regress; liver enzymes in serum remained elevated. Rats receiving a diet with 50000 ppm HMB showed markedly lower epididymal sperm density and an increase in the length of the estrous cycle at the end of the 13-week studies. In 2-week dermal studies, rats received topical applications of 1.25 to 20 mg of HMB in an acetone or lotion vehicle. The only effects noted were small and variable increases in liver and kidney weights, reaching statistical significance primarily in the higher dose groups. In 13-week studies, rats received topical doses from 12.5 to 200 mg/kg HMB in acetone. Kidney weights were elevated in dosed groups of female rats. No other findings were attributed to HMB treatment. In 2- and 13-week dosed feed studies, mice received feed containing 0, 3125, 6250, 12500, 25000, or 50000 ppm HMB. A dose- related increase in liver weight associated with hepatocyte cytoplasmic vacuolization was the only finding in mice in the 2- week studies. Decreased body weight gains were dose-related in mice in the 13-week studies; mild increases in liver weights were seen in dosed mice of both sexes. Kidney weights were increased variably in dosed females. Microscopic lesions were noted only in the kidneys of males receiving 50000 ppm HMB; these included eosinophilic protein casts in dilated renal tubules and a mild inflammation associated with the dilated tubules. Mice in the highest dose group exhibited a decrease in epididymal sperm density and an increase in length of the estrous cycle. In 2-week dermal studies, mice received topical applications from 0.5 to 8 mg HMB in an acetone or lotion vehicle. The only effects noted were minimal, variable increases in liver and kidney weights, primarily in the higher dose groups. In 13-week studies, mice received topical doses of 22.75 to 364 mg/kg in acetone. Kidney weights were increased variably in dosed male mice. Epididymal sperm density was decreased at all 3 dose levels evaluated (22.75, 91, and 200 mg/kg). The genetic toxicity of HMB also was evaluated in mutagenicity studies with Salmonella typhimurium, in cytogenetic studies with Chinese hamster ovary (CHO) cells, and by evaluation of micronucleated erythrocytes in peripheral blood smears from mice in the 13-week studies. HMB was weakly mutagenic in Salmonella with metabolic activation, and induced sister-chromatid exchanges and chromosomal aberrations in CHO cells in the presence of a metabolic activation system. There was no increase in the frequency of micronucleated erythrocytes in the blood of mice receiving HMB. In summary, HMB produced generally similar effects following topical and oral administration to rats and mice. Consistent findings included decreases in epididymal sperm density, lengthened estrous cycle, and increased liver and kidney weights. Mice in the dosed feed studies exhibited microscopic changes in the kidneys, comprising tubular dilatation with eosinophilic protein casts. Dilatation, tubular regeneration, papillary degeneration, and inflammation were noted in the kidneys of rats; and liver lesions consisting of an apparently reversible hepatocyte cytoplasmic vacuolization occurred in both rats and mice. A no-observed-adverse-effect level (NOAEL) for microscopic lesions was 6250 ppm HMB in the diet for rats and mice. A NOAEL was not reached for decreased epididymal sperm density in the 13- week dermal study in mice (<23 mg/kg/day). Synonyms: Oxybenzone; 4-Methoxy-2-hydroxy-benzophenone; Cyasorb UV; Uvinul M 40; (2-hydroxy-4-methoxyphenyl)phenyl-methanone; NSC-7778; Spectra-sorb UV; Syntase 62; UF 3; USAF CY-9; NCI-C60957.

Journal Article↗
PubMed1992

NTP technical report on the toxicity studies of Diethanolamine (CAS No. 111-42-2) Administered Topically and in Drinking Water to F344/N Rats and B6C3F1 Mice.

Diethanolamine is a high-production chemical used in cosmetics, in cutting fluids, as a dispersing agent for agricultural chemicals, and as an absorbent for acidic gases. Toxicology studies of diethanolamine were conducted in F344/N rats and B6C3F1 mice of both sexes for 2 weeks (5/sex/species/dose) and 13 weeks (10/sex/species/dose) to characterize and compare the effects of oral and dermal exposure. In addition to histopathology, evaluations included clinical pathology, urinalyses, and sperm morphology or vaginal cytology. In vitro genetic toxicity studies included assessments of mutagenicity in Salmonella typhimurium and mouse lymphoma L5178Y cells, analysis of chromosomal aberrations and sister chromatid exchange in Chinese hamster ovary cells, and determination of micronuclei formed in mice during the 13-week dermal exposure study. Groups of rats and mice received drinking water containing diethanolamine at concentrations of up to 10000 ppm during studies of 2 or 13 weeks duration. In the 2-week studies, rats and mice of both sexes received in the were 0, 630, 1250, 5000, and 10000 ppm diethanolamine in the drinking water. In the 13-week studies, rats received 0, 320, 630, 1250, 2500, and 5000 ppm (males) or 0, 160, 320, 630, 1250, and 2500 ppm (females) in drinking water; male and female mice received 0, 630, 1250, 2500, 5000, and 10000 ppm. All female rats in the 2 highest dose groups and 2 males in the 10000 ppm group in the 2-week study died before the end of the study. In the 13-week study, deaths of mice occurred in the 3 highest dose groups; 2 male rats in the top dose group also died. Surviving animals in the higher concentration groups in both studies exhibited depressed weight gains. Rats receiving diethanolamine developed a poorly regenerative, microcytic anemia in both studies. In the 2-week study, dosed male and female rats had increased kidney weights, renal tubular cell necrosis, and decreased renal function; rats in the 13-week study also showed increased incidences or severity of nephropathy, tubular necrosis, and mineralization. Degeneration of the seminiferous tubules of the testis was noted in dosed males in both the 2- and 13-week studies, and sperm motility and count were decreased in the 13-week study. Demyelination in the brain (medulla oblongata) and spinal cord was observed in male and female rats in the 13-week study. In mice, dose-dependent increases in liver weight were observed in males and females in the 2-week study; cytologic alteration and necrosis of individual hepatocytes were observed in the highest dose group. In the 13-week drinking water study in mice, nephropathy and tubular necrosis were observed in males, and degeneration of cardiac myocytes, and hepatocellular necrosis were seen in males and females. Cytologic alteration in the submandibular salivary gland was noted in male and female mice. Hepatocyte cytologic alteration also was noted in all dosed groups of mice. In the 2-week dermal studies, groups of rats and mice were administered daily doses of diethanolamine in 95% ethanol, ranging from 160 to 2500 mg/kg for mice, and from 125 to 2000 mg/kg for rats, 5 days per week. In 13-week studies, dermal doses ranged from 32 to 500 mg/kg for rats, and from 80 to 1250 mg/kg for mice. In the 2-week study, early deaths of male rats and male and female mice occurred in the highest dose groups and in female rats in the 2 highest dose groups (1000 and 2000 mg/kg). Body weight gains were reduced in rats and mice in the higher dose groups. Early deaths in the 13-week study were observed in the highest dose groups of rats (500 mg/kg) and mice (1250 mg/kg). Body weight gains were reduced in rats and mice given the higher doses. Rats in the dermal studies exhibited dose-dependent hematologic and renal function changes similar to those observed in rats in the drinking water study. In addition, in the 2-week study, rats exhibited ulcerative skin lesions at the site of application, accompanied by inflammatory cell infiltration, hyperkeratosis, and acanthosis (hyperplasia) of the epidermis.dermis. Hyperkeratosis, without ulceration, was observed in some animals. Ulceration at the site of application was observed in male and female mice. Acanthosis, without ulceration or inflammatory cell infiltration, was observed in mice in all lower dose groups. In the 13-week study, skin lesions at the site of application included ulceration and inflammation, hyperkeratosis, and acanthosis. Liver weights were increased in male and female rats, but there were no associated histopathological changes. Other treatment-related effects observed in rats included demyelination in the brain and spinal cord, and nephropathy, renal tubular necrosis, and/or tubular mineralization; mice exhibited cytological alterations in the liver and/or hepatocellular necrosis, renal tubular epithelial necrosis, and cardiac myocyte degeneration. In in vitro genetic toxicity studies, diethanolamine was not mutagenic in Salmonella typhimurium or mouse L5178Y TK&plusmn; cells. Diethanolamine did not induce sister-chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells, nor did it induce micronuclei in peripheral blood erythrocytes in mice exposed by topical application for 13 weeks. All in vitro studies were conducted with and without S9 activation. Target organs of diethanolamine toxicity identified in these studies included bone marrow, kidney, brain, spinal cord, testis, and skin in rats, and liver, kidney, heart, salivary gland, and skin in mice. A no-observed-adverse-effect-level (NOAEL) was not achieved for hematological changes or nephropathy in rats (<160 ppm), or for cytologic alteration of the liver in mice (<630 ppm) in the drinking water studies. In the dermal studies, a NOAEL was not achieved for hematological changes, nephropathy, or hyperkeratosis of the skin in rats (<32 mg/kg), or for cytologic alteration of the liver or acanthosis of the skin in mice (<80 mg/kg). Synonyms: 2,2&vprime;-iminodiethanol; 2,2&vprime;-iminobisethanol; diethylolamine; bis(hydroxy-ethyl)amine; 2,2'dihydroxydiethylamine; 2,2&vprime;-aminodiethanol.

Journal Article↗
PubMed1992

NTP technical report on the toxicity studies of Formic Acid (CAS No. 64-18-6) Administered by Inhalation to F344/N Rats and B6C3F1 Mice.

Formic acid occurs in a variety of plants and fruits, mammalian tissues, and insect venoms. It is used industrially in preparing a variety of drugs, dyes, and chemicals; as a decalcifier; and in leather tanning. Formic acid also is an environmental contaminant of air and water and has been identified as the toxic intermediate (formate) in methanol poisoning. Two- and 13-week toxicity studies of formic acid were conducted in male and female F344/N rats and B6C3F1 mice by whole body inhalation exposure to formic acid vapors. In addition, in vitro genetic toxicity studies were performed with Salmonella typhimurium, with or without metabolic activation. Formic acid was not mutagenic in this assay. In 2-week studies, groups of 5 F344/N rats and 5 B6C3F1 mice of each sex were exposed to formic acid for 6 hours a day, 5 days a week, at concentrations of 0, 31, 62.5, 125, 250, or 500 ppm. Deaths occurred in animals exposed to 500 ppm (rats and mice) and 250 ppm (1 female mouse). Microscopic lesions in the respiratory and olfactory epithelia occurred in rats and mice exposed to 62.5 ppm and higher concentrations, with the severity related to the exposure concentration. The lesions consisted of squamous metaplasia, necrosis, and inflammation. Exposures had minimal or no effects on coagulation times, blood pH and electrolytes, or on concentrations and activities of urine analytes in rats during the 2-week studies. In 13-week studies, groups of 10 animals of each species and sex were exposed to formic acid at concentrations of 0, 8, 16, 32, 64, and 128 ppm for 6 hours a day, 5 days a week. Two mice, 1 male and 1 female, died in the 128 ppm groups. Body weight gains were significantly decreased in mice exposed to 64 and 128 ppm formic acid. Microscopic changes in rats and mice ranged from minimal to mild in severity and generally were limited to animals in the 128 ppm groups. Lesions related to exposure to formic acid consisted of squamous metaplasia and degeneration of the respiratory and olfactory epithelia, respectively. Hematologic and serum biochemical changes at interim and terminal time points were minimal to mild and, generally, were consistent with hemoconcentration. Overall, the effects of formic acid were consistent with those of irritant chemicals administered by inhalation exposure. The no-observed-adverse-effect level (NOAEL) for respiratory injury was 32 ppm in rats and mice. There was no significant evidence of systemic toxicity in these studies. Synonyms: Aminic Acid, Formylic Acid, Methanoic Acid, Hydrogen Carboxylic Acid.

Journal Article↗
PubMed1993

NTP technical report on the toxicity studies of Pesticide/Fertilizer Mixtures Administered in Drinking Water to F344/N Rats and B6C3F1 Mice.

Toxicity studies were performed with pesticide and fertilizer mixtures representative of groundwater contamination found in California and Iowa. The California mixture was composed of aldicarb, atrazine, 1,2-dibromo-3-chloropropane, 1,2- dichloropropane, ethylene dibromide, simazine, and ammonium nitrate. The Iowa mixture contained alachlor, atrazine, cyanazine, metolachlor, metribuzin, and ammonium nitrate. The mixtures were administered in drinking water (with 512 ppm propylene glycol) to F344/N rats and B6C3F1 mice of each sex at concentrations ranging from 0.1x to 100x, where 1x represented the median concentrations of the individual chemicals found in studies of groundwater contamination from normal agricultural activities. This report focuses primarily on 26-week toxicity studies describing histopathology, clinical pathology, neurobehavior/neuropathology, and reproductive system effects. The genetic toxicity of the mixtures was assessed by determining the frequency of micronuclei in peripheral blood of mice and evaluating micronuclei and sister chromatid exchanges in splenocytes from female mice and male rats. Additional studies with these mixtures that are briefly reviewed in this report include teratology studies with Sprague-Dawley rats and continuous breeding studies with CD-1 Swiss mice. In 26-week drinking water studies of the California and the Iowa mixtures, all rats (10 per sex and group) survived to the end of the studies, and there were no significant effects on body weight gains. Water consumption was not affected by the pesticide/fertilizer contaminants, and there were no clinical signs of toxicity or neurobehavioral effects as measured by a functional observational battery, motor activity evaluations, thermal sensitivity evaluations, and startle response. There were no clear adverse effects noted in clinical pathology (including serum cholinesterase activity), organ weight, reproductive system, or histopathologic evaluations, although absolute and relative liver weights were marginally increased with increasing exposure concentration in both male and female rats consuming the Iowa mixture. In 26-week drinking water studies in mice, one male receiving the California mixture at 100x died during the study, and one control female and one female in the 100x group in the Iowa mixture study also died early. It could not be determined if the death of either of the mice in the 100x groups was related to consumption of the pesticide/fertilizer mixtures. Water consumption and body weight gains were not affected in these studies, and no signs of toxicity were noted in clinical observations or in neurobehavioral assessments. No clear adverse effects were noted in clinical pathology, reproductive system, organ weight, or histopathologic evaluations of exposed mice. The pesticide/fertilizer mixtures, when tested over a concentration range similar to that used in the 26-week studies, were found to have no effects in teratology studies or in a continuous breeding assay examining reproductive and developmental toxicity. The California and Iowa pesticide mixtures were tested for induction of micronuclei in peripheral blood erythrocytes of female mice. Results of tests with the California mixture were negative. Significant increases in micronucleated normochromatic erythrocytes were seen at the two-highest concentrations (10x and 100x) of the Iowa mixture, but the increases were within the normal range of micronuclei in historical control animals. Splenocytes of male rats and female mice exposed to these mixtures were examined for micronucleus and sister chromatid exchange frequencies. Sister chromatid exchange frequencies were marginally increased in rats and mice receiving the California mixture, but neither species exhibited increased frequencies of micronucleated splenocytes. None of these changes were considered to have biological importance. In summary, studies of potential toxicity associated with the consumption of mixtures of pesticides and a fertilizer representative of groundwater contamination in agriculturative of groundwater contamination in agricultural areas of Iowa and California failed to demonstrate any significant adverse effects in rats or mice receiving the mixtures in drinking water at concentrations as high as 100 times the median concentrations of the individual chemicals determined by groundwater surveys. 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↗