Search PubMed⌕ Search

Biomedical subjects

National Toxicology Program

Publications and source records attributed to National Toxicology Program.

At least 37 records · Page 2Linked to original sources
PubMed2004

NTP technical report on the toxicology and carcinogenesis studies of Stoddard Solvent IIC (Cas No. 64742-88-7) in F344/N rats and B6C3F1 mice (inhalation studies).

UNLABELLED: Stoddard solvent (white spirit/mineral spirit) is the most widely used solvent in the paint industry. It is used as a dry cleaning agent; as an extraction, cleaning, and degreasing solvent; and as a solvent in aerosols, paints, wood preservatives, asphalt products, lacquers, and varnishes. Stoddard solvent IIC was nominated by the International Union, United Auto Workers, for carcinogenicity testing because of the large volume used in industrial and other settings. Male and female F344/N rats and B6C3F1 mice were exposed to Stoddard solvent IIC (greater than 99% pure) by inhalation for 2 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and mouse peripheral blood erythrocytes. 2-WEEK STUDY IN RATS: Groups of five male and five female rats were exposed to Stoddard solvent IIC by inhalation at concentrations of 0, 138, 275, 550, 1,100, or 2,200 mg/m3, 6 hours per day, 5 days per week for 16 days. All rats survived to the end of the study, and mean body weights of all exposed groups were similar to those of the chamber controls. Liver weights of males exposed to 550 mg/m3 or greater and of females exposed to 275 mg/m3 or greater were increased. Minimal diffuse cytoplasmic vacuolization of hepatocytes of the liver occurred in all females exposed to 2,200 mg/m3. 2-WEEK STUDY IN MICE: Groups of five male and five female mice were exposed to Stoddard solvent IIC by inhalation at concentrations of 0, 138, 275, 550, 1,100, or 2,200 mg/m3, 6 hours per day, 5 days per week for 17 days. All mice survived to the end of the study, and mean body weights of all exposed groups were similar to those of the chamber controls. Liver weights of males and females exposed to 275 mg/m3 or greater were significantly increased. Cytomegaly of the liver occurred in all males and females exposed to 2,200 mg/m3. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to Stoddard solvent IIC by inhalation at concentrations of 0, 138, 275, 550, 1,100, or 2,200 mg/m3, 6 hours per day, 5 days per week for 14 weeks. All rats survived to the end of the study, and the final mean body weight of females exposed to 275 mg/m3 was greater than that of the chamber controls. The relative kidney, liver, and testis weights of all exposed groups of males and the absolute kidney weights of males exposed to 550 mg/m3 or greater were increased. The sperm motility of 550 mg/m3 or greater males was significantly decreased. The incidences of renal tubule granular casts were significantly increased in males exposed to 550 mg/m3 or greater, and the severities of renal tubule hyaline droplet accumulation, granular casts, and regeneration increased with increasing exposure concentration in males. The incidences of goblet cell hypertrophy of the nasal respiratory epithelium in males and females exposed to 2,200 mg/m3 were significantly increased. Sperm motility was decreased in males exposed to 550 mg/m3 or greater. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to Stoddard solvent IIC by inhalation at concentrations of 0, 138, 275, 550, 1,100, or 2,200 mg/m3, 6 hours per day, 5 days per week for 14 weeks. Mean body weights of exposed groups were similar to those of the chamber controls, but liver weights of males exposed to 2,200 mg/m3 were significantly increased. The sperm motility of 2,200 mg/m3 males was significantly decreased. This reduction in sperm motility, while statistically significant, is probably of modest importance as studies in mice have found that fertility is unaffected by motility decreases of less than 40%. The incidences of hematopoietic cell proliferation of the spleen in all exposed groups of females were greater than that in the chamber controls. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to Stoddard solvent IIC by inhalation at concentrations of 0, 138 (males), 550, 1,100, or 2,200 (females) mg/m3, 6 hours per day, 5 days per week for 104 to 105 weeks. Additional groups of 10 males and 10 females were exposed to the same concentrations for 3 months for renal toxicity analyses. Survival in the top exposure concentration groups of males and females was significantly less than that of the chamber controls. Mean body weights of exposed males and females were similar to those of the chamber controls. Cell proliferation analyses were performed in the left kidney of males and females after 3 months of exposure. The mean numbers of labeled cells and the labeling indices in males exposed to 550 and 1,100 mg/m3 were significantly increased. The amount of alpha2u-globulin in the right kidney of males increased with increasing exposure concentration. Also, the incidences of granular casts and cortical tubule degeneration and regeneration were generally increased in exposed males, as was the severity of hyaline droplets. These effects did not occur in females. At 2 years, the incidences of benign and benign or malignant pheochromocytoma (combined) of the adrenal medulla occurred with positive trends in males, and the incidences in the 550 and 1,100 mg/m3 groups were significantly increased. Due to increased incidences of renal tubule hyperplasia in males at 2 years, extended kidney evaluations were conducted; a slightly increased incidence of renal tubule adenoma occurred in the 1,100 mg/m3 group. Nonneoplastic lesions related to Stoddard solvent IIC exposure occurred in the kidney of males. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to Stoddard solvent IIC by inhalation at concentrations of 0, 550, 1,100, or 2,200 mg/m3, 6 hours per day, 5 days per week for 105 weeks. Survival of exposed mice was similar to that of the chamber controls. Mean body weights of exposed females were greater than those of the chamber controls. The incidences of hepatocellular adenoma occurred with a positive trend in females, and the incidence of multiple hepatocellular adenoma in females exposed to 2,200 mg/m3 was significantly increased. However, the incidences of hepatocellular adenoma or carcinoma (combined) and hepatocellular carcinoma alone in exposed males and females were not significantly increased. GENETIC TOXICOLOGY: Stoddard solvent IIC was tested for mutagenicity in Salmonella typhimurium strains TA97, TA98, TA100, and TA1535, with and without S9 metabolic activation enzymes; all results were negative. In vivo, the frequency of micronucleated erythrocytes was assessed in peripheral blood samples from male and female B6C3F1 mice after 3 months of inhalation exposure to Stoddard solvent IIC, and results were negative. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was some evidence of carcinogenic activity of Stoddard solvent IIC in male F344/N rats based on increased incidences of adrenal medulla neoplasms; the slightly increased incidences of renal tubule adenoma may have been related to Stoddard solvent IIC exposure. There was no evidence of carcinogenic activity of Stoddard solvent IIC in female F344/N rats exposed to 550, 1,100, or 2,200 mg/m3. There was no evidence of carcinogenic activity of Stoddard solvent IIC in male B6C3F1 mice exposed to 550, 1,100, or 2,200 mg/m3. There was equivocal evidence of carcinogenic activity of Stoddard solvent IIC in female B6C3F1 mice based on increased incidences of hepatocellular adenoma; this slight increase was associated with increased body weight in exposed females. Exposure of male rats to Stoddard solvent IIC resulted in nonneoplastic lesions of the kidney characteristic of alpha2u-globulin accumulation.

Adrenal Gland Neoplasms↗
PubMed2004

NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Fluoxetine.

The National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (CERHR) conducted an evaluation of the potential for fluoxetine to cause adverse effects on reproduction and development in humans. Fluoxetine (Prozac(R); Serafemtrade mark) was selected for evaluation because of 1) sufficient reproductive and developmental studies, 2) human exposure information, 3) changing prescription patterns, and 4) public concern about potential reproductive and/or developmental hazards associated with exposure. Fluoxetine, an antidepressant, is also prescribed to treat premenstrual dysphoric disorder and has recently been approved for use in 7-17 year-olds. The results of this evaluation on fluoxetine are published in an NTP-CERHR monograph which includes: 1) the NTP Brief, 2) the Expert Panel Report on the Reproductive and Developmental Toxicity of Fluoxetine, and 3) public comments received on the Expert Panel Report. As stated in the NTP Brief, the NTP reached the following conclusions regarding the possible effects of exposure to fluoxetine on human development and reproduction. First, there is some concern for developmental effects, specifically shortened gestation and poor neonatal adaptation at therapeutic doses (20-80 mg/day). This conclusion is based on evidence from human studies that fluoxetine produces an increased rate of poor neonatal adaptation and that fluoxetine exposure during pregnancy can result in a shortened gestation and reduced birth weight at term. Second, there is minimal concern for adverse reproductive effects in fluoxetine-exposed adults. Evidence from human studies show that therapeutic doses of fluoxetine may, in both men and women, result in reversible, impaired sexual function, specifically a delay in or an inability to achieve orgasm. Finally, there are insufficient data to draw conclusions on 1) an association between fluoxetine therapy in pregnant women and pregnancy loss; and 2) on how breast milk or therapeutic exposures to fluoxetine might affect development. In a study in mice, early fluoxetine exposure affected adult behavior. However, additional data are needed to confirm and extend these findings and determine if such effects might possibly occur in humans. NTP-CERHR monographs are transmitted to federal and state agencies, interested parties, and the public and are available in electronic PDF format on the CERHR web site (http://cerhr.niehs.nih.gov) and in printed text or CD-ROM from the CERHR (National Institute of Environmental Health Sciences, P.O. Box 12233, MD EC-32, Research Triangle Park, NC; fax: 919-316-4511).

Journal Article↗
PubMed2004

NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Propylene Glycol (PG).

The National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (CERHR) conducted an evaluation of the potential for propylene glycol (PG) to cause adverse effects on reproduction and development in humans. PG was selected for evaluation because of the potential for widespread human exposure through its use in food, tobacco, pharmaceutical products, cosmetics, various paints and coatings and as an antifreeze and de-icing solution. PG is a small, hydroxy-substituted hydrocarbon used as a chemical intermediate in the production of unsaturated polyester resins and in the production of plasticizers. The results of this evaluation on PG are published in an NTP-CERHR monograph which includes: 1) the NTP Brief, 2) the Expert Panel Report on the Reproductive and Developmental Toxicity of Propylene Glycol, and 3) public comments received on the Expert Panel Report. As stated in the NTP Brief, the NTP reached the following conclusions regarding the possible effects of exposure to PG on human development and reproduction. There is negligible concern for adverse developmental and reproductive effects in humans at current, proposed, or estimated exposure levels. There is no direct evidence that exposure of people to PG adversely affects reproduction or development. Studies in pregnant laboratory animals at oral doses of PG greater than 1,200 mg/kg body weight/ day and up to 10,400 mg/kg body weight/day in mice, did not produce developmental toxicity in offspring. In a continuous breeding study, no effects on fertility were observed in male or female mice at doses up to 10,100 mg/kg body weight/day in drinking water. The pharmacokinetics of PG indicates that the lack of adverse effects observed in laboratory animals is relevant to humans. The rate-limiting step in PG metabolism is conversion to the more toxic lactaldehyde product by alcohol dehydrogenase. Studies indicate that this enzyme saturates in humans at doses 8-10- fold lower than in rats and rabbits, thus affording less toxicity in humans. It is estimated that the average daily intake of PG from food products in the US is 34 mg/kg body weight/day for a 70 kg person, which is over 300 -fold lower than the highest dose tested in laboratory animals. NTP-CERHR monographs are transmitted to federal and state agencies, interested parties, and the public and are available in electronic PDF format on the CERHR web site (http://cerhr.niehs.nih.gov) and in printed text or CD-ROM from the CERHR (National Institute of Environmental Health Sciences, P.O. Box 12233, MD EC-32, Research Triangle Park, NC; fax: 919-316-4511).

Journal Article↗
PubMed2004

NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Ethylene Glycol.

The National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (CERHR) conducted an evaluation of the potential for ethylene glycol (EG) to cause adverse effects on reproduction and development in humans. EG was selected for evaluation due to recent toxicity and occupational exposure information and widespread exposure in the general public. EG is a small, hydroxy-substituted hydrocarbon used as a chemical intermediate in the production of polyester compounds. It is also found in automotive anti-freeze, industrial coolants, hydraulic fluids, and windshield deicer fluids. The results of this evaluation on EG are published in a NTP-CERHR monograph which includes: 1) the Expert Panel Report on the Reproductive and Developmental Toxicity of Ethylene Glycol, 2) the NTP Brief, and 3) public comments received on the Expert Panel Report. As stated in the NTP Brief, the NTP reached the following conclusions regarding the possible effects of exposure to EG on human development and reproduction based on the conclusions of the NTP-CERHR Expert Panel Report and the public comments received on that report. These conclusions concurred with those of the expert panel. First, although EG could possibly affect human development if exposures are sufficiently high, there is negligible concern for developmental effects in humans at current proposed/estimated exposure levels. There is no direct evidence that exposure of people to EG adversely affects reproduction or development, but studies reviewed by the expert panel show that oral exposure to high doses of EG can adversely affect development in mice and rats. These studies indicate doses that exceed saturation of the glycolic acid metabolism are needed to produce developmental toxicity. Proposed exposure scenarios constructed by the expert panel and current proposed/estimated exposure levels suggest that human exposures are at least 100- to 1000-fold lower than the dose expected to result in metabolic saturation in humans (estimated at 125 mg/kg body weight). Second, there is negligible concern for reproductive effects in humans. Studies evaluated by the expert panel showed that, at high exposure levels, there is no evidence of adverse reproductive effects in mice or rats. NTP-CERHR monographs are transmitted to federal and state agencies, interested parties, and the public and are available electronically in PDF format on the CERHR web site (http://cerhr.niehs.nih.gov) and in printed text or CD-ROM from the CERHR (National Institute of Environmental Health Sciences, P.O. Box 12233, MD EC-32, Research Triangle Park, NC; fax: 919-316-4511).

Journal Article↗
PubMed2003

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

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

Acyclic Monoterpenes↗
PubMed2003

Toxicology and carcinogenesis studies of riddelliine (CAS No. 23246-96-0) in F344/N rats and B6C3F1 mice (gavage studies).

UNLABELLED: Riddelliine belongs to a class of toxic pyrrolizidine alkaloids and is isolated from plants of the genera Crotalaria, Amsinckia, and Senecio that grow in the western United States. Cattle, horses, and sheep that ingest these plants succumb to their toxic effects. Riddelliine residues have been found in meat, milk, and honey, and the plants may contaminate human food sources. Riddelliine was nominated for study by the Food and Drug Administration because of its potential for human exposure and its economic impact on the livestock industry and because the toxicity of other pyrrolizidine alkaloids suggests riddelliine may be carcinogenic. Male and female F344/N rats and B6C3F1 mice received riddelliine (approximately 92% pure) by gavage. Female rats and male and female mice were dosed for 2 years; due to high mortality, the study in male rats was terminated at week 72. In vitro genetic toxicology studies were conducted in Salmonella typhimurium and in cultured Chinese hamster ovary (CHO) cells. In addition, riddelliine was evaluated in vivo for induction of micronuclei in mouse bone marrow and peripheral blood erythrocytes and for induction of S-phase DNA synthesis and unscheduled DNA synthesis in the liver of rats and mice. Riddelliine-induced DNA adduct levels were determined in liver tissue obtained from female rats admininstered riddelliine for 3 or 6 months. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were administered 0 or 1 mg riddelliine/kg body weight in sodium phosphate buffer by gavage 5 days per week; additional groups of 50 female rats received 0.01, 0.033, 0.1, or 0.33 mg/kg. A wide dose range was used in female rats to better characterize the dose-response curve. Females were dosed for 105 weeks; due to high mortality, male rats were terminated at week 72. All but three 1 mg/kg males died before week 70, and all 1 mg/kg females died before week 97. Mean body weights of 1 mg/kg males and females were less than those of the vehicle controls throughout most of the study. The only clinical finding related to riddelliine administration was a general debilitation of the animals prior to death. Hemangiosarcomas were present in the liver of 86% of males and 76% of females in the 1 mg/kg groups, and this neoplasm was considered the cause of the large number of early deaths in these groups. The incidences of hepatocellular adenoma and mononuclear cell leukemia in 1 mg/kg males and females were significantly increased. Nonneoplastic lesions related to riddelliine treatment occurred in the liver and kidney of males and females. Analyses of liver tissue from female rats treated with riddelliine for 3 or 6 months yielded eight DNA adducts; these were the same as DNA adducts formed in vitro by the metabolism of riddelliine by human liver microsomes in the presence of calf thymus DNA. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were administered riddelliine in sodium phosphate buffer by gavage at doses of 0 or 3 mg/kg, 5 days per week, for 105 weeks; additional groups of 50 male mice received 0.1, 0.3, or 1 mg/kg for 105 weeks. A wide dose range was used in male mice to better characterize the dose-response curve. Survival of males and females administered 3 mg/kg was significantly less than that of the vehicle controls. Mean body weights of 3 mg/kg mice were less than those of the vehicle controls throughout most of the study. Hemangiosarcomas of the liver were present in 62% of males in the 3 mg/kg group. The incidences of hepatocellular neoplasms occurred with negative trends in male mice and were significantly decreased in 3 mg/kg females. The incidences of alveolar/bronchiolar neoplasms in 3 mg/kg females were significantly increased. Nonneoplastic lesions related to riddelliine administration occurred in the liver and kidney of males and females and in the lung and arteries (multiple tissues) of females. GENETIC TOXICOLOGY: Riddelliine was mutagenic in S. typhimurium strain TA100 with, but not without, S9 activation; no significant mutagenic activity was detected in strain TA98 or TA1535,ed in strain TA98 or TA1535, with or without S9. A small, dose-related increase in mutant colonies seen in strain TA97 with S9 was judged to be equivocal. Riddelliine induced sister chromatid exchanges in cultured CHO cells with and without S9. Chromosomal aberrations were induced in CHO cells only in the presence of S9. Following 4 or 13 weeks of daily gavage treatment with riddelliine, no increases in the frequency of micronucleated erythrocytes were noted in the peripheral blood of male or female B6C3F1 mice. Use of a single intraperitoneal injection protocol, however, produced a small but significant increase in the frequency of micronucleated eryth-rocytes in peripheral blood of male Swiss mice 48 hours after injection; bone marrow analysis 24 hours after injection demonstrated a small but insignificant increase in the frequency of micronuclei. 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 S-phase DNA synthesis was observed in cultured hepatocytes of male and female rats treated for either time period. CONCLUSIONS: Under the conditions of these studies, there was clear evidence of carcinogenic activity of riddelliine in male and female F344/N rats based primarily on increased incidences of hemangiosarcoma in the liver. The increased incidences of hepatocellular adenoma and mononuclear cell leukemia in male and female rats were also considered to be treatment related. There was clear evidence of carcinogenic activity of riddelliine in male B6C3F1 mice based on increased incidences of hemangiosarcoma in the liver. There was clear evidence of carcinogenic activity in female B6C3F1 mice based on increased incidences of alveolar/bronchiolar neoplasms. Administration of riddelliine by gavage resulted in nonneoplastic lesions in the liver and kidney of male and female rats; the liver and kidney of male and female mice; and the lung and arteries (multiple tissues) of female mice. Decreased incidences of hepatocellular neoplasms in male and female mice were related to riddelliine administration.

Adenoma, Liver Cell↗
PubMed2003

NTP toxicology and carcinogensis Studies of 2,4-hexadienal (89% trans,trans isomer, CAS No. 142-83-6; 11% cis,trans isomer) (Gavage Studies).

UNLABELLED: 2,4-Hexadienal, a colorless to yellow liquid with a pungent "green" or citrus odor, is used as a food additive for flavor enhancement, as a fragrance agent, as a starting material or intermediate in synthetic reactions in the chemical and pharmaceutical industries, as a fumigant, and as a corrosion inhibitor for steel. 2,4-Hexadienal was nominated for study by the National Cancer Institute because of the potential for carcinogenicity based on its alpha,beta-unsaturated aldehyde structure and the potential link between exposure to lipid peroxidation products in the diet and human malignancies. The commercial product is a mixture containing chiefly trans,trans-2,4-hexadienal in equilibrium with cis,trans-2,4-hexadienal. Male and female F344/N rats and B6C3F1 mice received 2,4-hexadienal (89% trans,trans; 11% cis,trans) in corn oil by gavage for 16 days, 14 weeks, or 2 years. Tissues and plasma from dosed rats were examined for malondialdehyde and glutathione concentrations, and DNA adducts were characterized in liver and forestomach samples from dosed rats and mice. Genetic toxicology studies were conducted in Salmonella typhimurium, rat and mouse bone marrow cells, and mouse peripheral blood erythrocytes. 16-DAY STUDY IN RATS: Groups of five male and five female rats were administered 0, 3, 9, 27, 80, or 240 mg 2,4-hexadienal/kg body weight in corn oil by gavage, 5 days per week, for 16 days. Three male and three female 240 mg/kg rats died before the end of the study. Mean body weight gains of 240 mg/kg rats were significantly less than those of the vehicle controls. Clinical findings included diarrhea, ataxia, lethargy, and nasal/eye discharge in males, and lethargy, paleness, and abnormal breathing in females in the 240 mg/kg groups. Liver weights of 240 mg/kg females were significantly greater than those of the vehicle controls. Gross and microscopic lesions indicative of forestomach necrosis and ulceration were present in most 240 mg/kg rats, and forestomach epithelial hyperplasia was microscopically evident in most 80 mg/kg rats. 16-DAY STUDY IN MICE: Groups of five male and five female mice were administered 2,4-hexadienal in corn oil by gavage at doses of 0, 3, 9, 27, 80, or 240 mg/kg, 5 days per week, for 16 days. Chemical-related deaths occurred in one male and one female in the 240 mg/kg groups. Female mice in the 240 mg/kg group lost weight during the study. Gross and microscopic lesions indicative of forestomach necrosis and ulceration were present in all 240 mg/kg mice, and forestomach epithelial hyperplasia and hyperkeratosis were microscopically evident in 80 mg/kg mice. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were administered 2,4-hexadienal in corn oil by gavage at doses of 0, 7.5, 15, 30, 60, or 120 mg/kg, 5 days per week, for 14 weeks. All rats survived to the end of the study. Mean body weights of 30, 60, and 120 mg/kg males were significantly less than those of the vehicle controls. The only clinical finding attributed to 2,4-hexadienal administration was hypersalivation in 30 and 120 mg/kg males and females. The incidences of forestomach hyperplasia and nasal olfactory atrophy or necrosis were significantly increased in 120 mg/kg rats. Nasal lesions occurred in most 120 mg/kg male rats. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were administered 2,4-hexadienal in corn oil by gavage at doses of 0, 7.5, 15, 30, 60, or 120 mg/kg, 5 days per week, for 14 weeks. No deaths were attributed to administration of 2,4-hexadienal. Mean body weights of males and females were similar to those of the vehicle controls throughout the study. Clinical findings included salivation and anal wetness in males and females. Kidney weights of 60 and 120 mg/kg males and liver weights of 60 mg/kg males and females were significantly greater than those of the vehicle controls. The incidences of forestomach hyperplasia and/or nasal olfactory atrophy or necrosis were significantly increased in 120 mg/kg mice. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were administered 2,4-hexministered 2,4-hexadienal in corn oil by gavage at doses of 0, 22.5, 45, or 90 mg/kg, 5 days per week, for up to 105 weeks. Survival of all dosed groups of rats was similar to that of the vehicle control groups. The mean body weights of 90 mg/kg males were generally less than those of the vehicle controls throughout the study. The incidences of squamous cell papilloma of the forestomach occurred with positive trends in male and female rats. This neoplasm was found in 58% of males and 34% of females in the 90 mg/kg groups. In the forestomach of male rats, papilloma multiplicity was increased in the 90 mg/kg group, and squamous cell carcinomas were found in one 45 mg/kg male and two 90 mg/kg males. Epithelial hyperplasia of the forestomach occurred in most 45 and 90 mg/kg rats. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were administered 2,4-hexadienal in corn oil by gavage at doses of 0, 30, 60, or 120 mg/kg, 5 days per week, for up to 105 weeks. Survival of dosed mice was similar to that of the vehicle controls. The mean body weights of all dosed groups were generally similar to those of the vehicle controls throughout the study. The incidences of squamous cell papilloma of the forestomach occurred with positive trends in male and female mice; squamous cell carcinomas were present in 120 mg/kg males and females. Epithelial hyperplasia of the forestomach occurred in many 120 mg/kg mice. Two 120 mg/kg males had uncommon squamous cell carcinoma of the oral cavity (tongue). GENETIC TOXICOLOGY: 2,4-Hexadienal was mutagenic in S. typhimurium strain TA100 with and without induced hamster or rat liver enzymes; no mutagenic activity was detected with strains TA1535 or TA98, with or without S9. Results of bone marrow tests in male rats and male mice given intraperitoneal injections of 2,4-hexadienal showed a small increase in the induction of micronucleated erythrocytes. However, neither test was repeated, and the test results were judged to be inconclusive. Results of peripheral blood micronucleus tests in male and female mice treated with 2,4-hexadienal by gavage for 14 weeks were negative. CONCLUSIONS: Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity* of 2,4-hexadienal in male and female F344/N rats and male and female B6C3F1 mice based on increased incidences of squamous cell neoplasms of the forestomach. The occurrence of squamous cell carcinoma of the oral cavity (tongue) in male B6C3F1 mice may have been related to the administration of 2,4-hexadienal. Hyperplasia of the forestomach in male and female rats and mice was associated with administration of 2,4-hexadienal. Synonyms: Hexa-2,4-dienal; 2,4-hexadienal; 2,4-hexadien-1-al; 2,4-Hx; 1,3-pentadiene-1-carboxaldehyde; 2-propylene acrolein; sorbaldehyde; sorbic aldehyde

Aldehydes↗
PubMed2003

NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Di-isononyl Phthalate (DINP).

The National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (CERHR) conducted an evaluation of the potential for di-isononyl phthalate (DINP) to cause adverse effects on reproduction and development in humans. DINP is one of 7 phthalate chemicals evaluated by the NTP CERHR Phthalates Expert Panel. These phthalates were selected for evaluation because of high production volume, extent of human exposures, use in children's products, and/or published evidence of reproductive or developmental toxicity. DINP is a mixture of branched, C-9 phthalate isomers used to add flexibility to a wide variety of plastic products such as toys, garden hoses, flooring tiles, tarps, and pool liners. The results of this evaluation on DINP are published in a NTP-CERHR monograph which includes: 1) the NTP Brief, 2) the Expert Panel Report on the Reproductive and Developmental Toxicity of Di-isononyl Phthalate, and 3) public comments received on the Expert Panel Report. As stated in the NTP Brief, the NTP reached the following conclusions regarding the possible effects of exposure to DINP on human development and reproduction. First, although DINP could possibly affect human development if exposures are sufficiently high, there is minimal concern for DINP causing adverse effects to human reproduction or fetal development. There is no direct evidence that exposure of people to DINP adversely affects reproduction or development, but studies show that oral exposure of pregnant rats to high doses (500 and 1000 mg/kg bodyweight/day) of DINP can adversely affect fetal development. Effects on pup growth were noted in a 2-generation reproductive toxicity study in rats at doses of 143-285 mg/kg body weight/day. Human exposure information for DINP was not available but it was assumed that the general US population would be exposed to 3-30 mug/kg body weight/day, based upon the range of estimated exposures for DEHP, a more widely used phthalate. Second, based on estimates of exposure of children to DINP from mouthing toys and other objects, the NTP has minimal concern for developmental effects in children. After the expert panel meeting, a US Consumer Products Safety Commission panel estimated that the majority of children exposed to DINP had a "minimum to non-existent risk of injury" from mouthing toys. Children's exposure was estimated at 70-280 mug/kg body weight/day, a level 1000-fold lower than exposures resulting in developmental effects in rats. NTP-CERHR monographs are transmitted to federal and state agencies, interested parties, and the public and are available electronically in PDF format on the CERHR web site (http://cerhr.niehs.nih.gov) and in printed text or CD-ROM from the CERHR (National Institute of Environmental Health Sciences, P.O. Box 12233, MD EC-32, Research Triangle Park, NC; fax: 919-316-4511).

Journal Article↗
PubMed2003

NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Di-Isodecyl Phthalate (DIDP).

The National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (CERHR) conducted an evaluation of the potential for di-isodecyl phthalate (DIDP) to cause adverse effects on reproduction and development in humans. DIDP is one of 7 phthalate chemicals evaluated by the NTP CERHR Phthalates Expert Panel. These phthalates were selected for evaluation because of high production volume, extent of human exposures, use in children's products, and/or published evidence of reproductive or developmental toxicity. DIDP is a mixture of branched, C-10 phthalate isomers used to add flexibility to a wide variety of polyvinylchloride (PVC) plastic products such as artificial leather, toys, carpet backing, and pool liners. The results of this evaluation on DIDP are published in a NTP-CERHR monograph which includes: 1) the NTP Brief, 2) the Expert Panel Report on the Reproductive and Developmental Toxicity of Di-Isodecyl Phthalate, and 3) public comments received on the Expert Panel Report. As stated in the NTP Brief, the NTP reached the following conclusions regarding the possible effects of exposure to DIDP on human development and reproduction. First, although DIDP could possibly affect human development if exposures are sufficiently high, there is minimal concern for developmental effects in fetuses and children at current proposed/estimated exposure levels. There is no direct evidence that exposure of people to DIDP adversely affects reproduction or development, but show that oral exposure of pregnant rats to high doses (200 and 1000 mg/kg bodyweight/day) of DIDP can adversely affect fetal development. Human exposure information for DIDP was not available, but it was assumed that the general US population would be exposed to 3-30 mug/kg body weight/day, based upon the range of estimated exposures for DEHP, a more widely used phthalate. Second, there is negligible concern for reproductive toxicity in exposed adults. Studies evaluated showed that, at high exposure levels, there is no evidence of adverse reproductive effects in rats. NTP-CERHR monographs are transmitted to federal and state agencies, interested parties, and the public and are available electronically in PDF format on the CERHR web site (http://cerhr.niehs.nih.gov) and in printed text or CD-ROM from the CERHR (National Institute of Environmental Health Sciences, P.O. Box 12233, MD EC-32, Research Triangle Park, NC; fax: 919-316-4511).

Journal Article↗
PubMed2003

NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Di-n-Octyl Phthalate (DnOP).

The National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (CERHR) conducted an evaluation of the potential for di-n-octyl phthalate (DnOP) to cause adverse effects on reproduction and development in humans. DnOP is one of 7 phthalate chemicals evaluated by the NTP CERHR Phthalates Expert Panel. These phthalates were selected for evaluation because of high production volume, extent of human exposures, use in children's products, and/or published evidence of repro- ductive or developmental toxicity. Available information indicates that there are no commercial uses of pure DnOP. However, DnOP comprises approximately 20% of the commercially important C6-10 phthalate mixture, which is used in flooring and carpet tiles, tarps, pool liners, and garden hoses. DnOP is approved by the FDA as an indirect food additive and is used in seam cements, bottle cap liners, and conveyor belts. The results of this evaluation on DnOP are published in an NTP-CERHR monograph which includes: 1) the NTP Brief, 2) the Expert Panel Report on the Reproductive and Developmental Toxicity of DnOP, and 3) public comments received on the Expert Panel Report. As stated in the NTP Brief, the NTP reached the following conclusions regarding the possible effects of exposure to DnOP on human development and reproduction. Limited studies in mice and rats show that high exposures to DnOP may cause adverse developmental effects, but no evidence of reproductive effects was observed. In a continuous breeding study, no adverse effects were observed in the treated parents or their offspring after dosed feed exposure of mice (approx. 1,800, 3,600, or 7,500 mg/kg body weight/day). Human exposure information for DnOP was not available but it was assumed that the general US population would be exposed to 3-30 mug/kg body weight/day, based upon the range of estimated exposures for DEHP. Based on this assumption, NTP concluded that there is negligible concern for effects on adult reproductive systems. Two developmental studies were evaluated by the panel. In the first study, pregnant rats were treated with 5,000 and 10,000 mg/kg body weight/day DnOP by intraperitoneal injection on gestational days 5, 10, and 15. Increased fetal malformations and reduced body weights were observed at both doses. In the second study, pregnant mice were treated by gavage with approx. 10,000 mg/kg bodyweight/day on gestational days 6-13 and were allowed to deliver the pups. The treated group had reduced litter size, but birth weights and pup survival to postnatal day 3 were not affected. These studies did not determine an exposure level at which no adverse effects occur. The NTP concluded that there is insufficient information on developmental toxicity to reach a conclusion regarding the potential for DnOP to adversely affect human development. NTP-CERHR monographs are transmitted to federal and state agencies, interested parties, and the public and are available in electronic PDF format on the CERHR web site (http://cerhr.niehs.nih.gov) and in printed text or CD-ROM from the CERHR (National Institute of Environmental Health Sciences, P.O. Box 12233, MD EC-32, Research Triangle Park, NC; fax: 919-316-4511).

Journal Article↗
PubMed2003

NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Di-n-Hexyl Phthalate (DnHP).

The National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (CERHR) conducted an evaluation of the potential for di-n-hexyl phthalate (DnHP) to cause adverse effects on reproduction and development in humans. DnHP is one of 7 phthalate chemicals evaluated by the NTP CERHR Phthalates Expert Panel. These phthalates were selected for evaluation because of high production volume, extent of human exposures, use in children's products, and/or published evidence of reproductive or developmental toxicity. Available information indicates that DnHP is manufactured in relatively small amounts but occurs in a variety of commercial products including dip-molded products such as tool handles or dishwasher baskets, flooring, vinyl gloves, flea collars, and conveyer belts used in food processing. The results of this evaluation on DnHP are published in an NTP-CERHR monograph which includes: 1) the NTP Brief, 2) the Expert Panel Report on the Reproductive and Developmental Toxicity of DnHP, and 3) public comments received on the Expert Panel Report. As stated in the NTP Brief, the NTP reached the following conclusions regarding the possible effects of exposure to DnHP on human development and reproduction. The scientific evidence was insufficient to reach a conclusion regarding the potential for DnHP to adversely affect human development or reproduction. There was very limited information on developmental and reproductive toxicity available to the panel. The panel evaluated only a single developmental toxicity study using a high dose (9,900 mg/kg body weight/day on gestational days 6-13) of DnHP. No live pups were delivered. In a reproductive study, effects on fertility were noted in all treatment groups (380-1,670 mg/ kg body weight/day). These studies provided sufficient information in experimental animals to conclude that DnHP is a reproductive and developmental toxicant at the doses tested. However, the treatment doses were high and these studies did not determine an exposure level at which no adverse effects occur. Human exposure information for DnHP was not available to the panel. However, the panel assumed that the US general population would be exposed to 3-30 mug/kg body weight/day, based upon the range of estimated exposures for DEHP, a more widely used phthalate. Thus, considering the inadequate quantitative information from the experimental animal studies and the inadequate human exposure data, the panel concluded there is insufficient information to reach a conclusion of the potential for DnHP to adversely affect human development or reproduction. NTP-CERHR monographs are transmitted to federal and state agencies, interested parties, and the public and are available in electronic PDF format on the CERHR web site (http://cerhr.niehs.nih.gov) and in printed text or CD-ROM from the CERHR (National Institute of Environmental Health Sciences, P.O. Box 12233, MD EC-32, Research Triangle Park, NC; fax: 919-316-4511).

Journal Article↗
PubMed2003

NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Methanol.

The National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (CERHR) conducted an evaluation of the potential for methanol to cause adverse effects on reproduction and development in humans. Methanol was selected for evaluation because it is a high production volume chemical with high potential for occupational, consumer, and environmental exposure. Methanol is used in chemical syntheses and as an industrial solvent. It is found in a variety of consumer products such as paints, antifreeze, cleaning solutions, and adhesives and is a by-product of sewage treatment, fermentation, and paper production. Methanol is used in racecar fuels, and there is the potential for the expanded use of methanol as a vehicle fuel or fuel additive. Methanol occurs naturally in a variety of fresh fruits and vegetables, alcoholic beverages, and cigarette smoke. The results of this evaluation on methanol are published in an NTP-CERHR monograph which includes: 1) the NTP Brief, 2) the Expert Panel Report on the Reproductive and Developmental Toxicity of Methanol, and 3) public comments received on the Expert Panel Report. As stated in the NTP Brief, the NTP reached the following conclusions regarding the possible effects of exposure to methanol on human development and reproduction. First, there is concern for adverse developmental effects in fetuses if pregnant women are exposed to levels of methanol that result in high blood concentrations, such as with acute methanol poisoning. Although there is insufficient evidence to determine if a human fetus is more or less sensitive than rodents to the adverse effect of methanol, humans suffering acute methanol poisoning may have blood levels similar to those resulting in developmental toxicity in rodents. Second, for exposures that result in low blood methanol concentrations (below approx. 10 mg/L blood), there is minimal concern for adverse developmental effects , and negligible concern for adverse male reproductive effects. There is insufficient evidence to assess the effects of methanol on female reproduction. Data available to the expert panel were not sufficient to rule out the possibility of male reproductive effects at toxic exposure levels. The panel judged that blood levels >/=10 mg/L are not expected to result from normal dietary or occupational exposures. NTP-CERHR monographs are transmitted to federal and state agencies, interested parties, and the public and are available in electronic PDF format on the CERHR web site (http://cerhr.niehs.nih.gov) and in printed text or CD-ROM from the CERHR (National Institute of Environmental Health Sciences, P.O. Box 12233, MD EC-32, Research Triangle Park, NC; fax: 919-316-4511).

Journal Article↗
PubMed2003

NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of 1-Bromopropane (1-BP).

The National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (CERHR) conducted an evaluation of the potential for 1-bromopropane to cause adverse effects on reproduction and development in humans. 1-Bromopropane was selected for evaluation due to recent consideration of 1-bromopropane as a replacement chemical for hydrochlorofluorocarbons and chlorinated solvents. 1-Bromopropane is used in spray adhesives and in cleaning metal and electronic components; as a solvent for fats, waxes, or resins; and as an intermediate in the synthesis of pharmaceuticals, insecticides, quaternary ammonium compounds, flavors, or fragrances. The results of this evaluation on 1-brompropane are published in a NTP-CERHR monograph which includes: 1) the NTP Brief, 2) the Expert Panel Report on the Reproductive and Developmental Toxicity of 1-Bromopropane, and 3) public comments received on the Expert Panel Report. As stated in the NTP Brief, the NTP reached the following conclusions regarding the possible effects of exposure to 1-bromopropane on human development and reproduction. No data were available on 1-bromopropane exposures in the general US population. Therefore, conclusions were based on the available occupational exposure data and on studies in humans and laboratory animals. First, there is serious concern for reproductive and developmental effects at the upper end of the human occupational exposure range (18-381 ppm). Adverse developmental and/or reproductive effects have been reported in animal studies at exposure levels of >/=200 ppm. Second, there is minimal concern for reproductive and developmental effects when humans are exposed at the lower end of the human occupational exposure range (0.04-0.63 ppm). This level is at least 300- fold lower than the no effect level identified from reproductive studies in laboratory animals. These conclusions are based upon limited occupational inhalation exposure data. It is likely that worker exposures also occur through dermal contact with 1-bromopropane. However, no information was available on dermal exposures. NTP-CERHR monographs are transmitted to federal and state agencies, interested parties, and the public and are available in electronic PDF format on the CERHR web site (http://cerhr.niehs.nih.gov) and in printed text or CD-ROM from the CERHR (National Institute of Environmental Health Sciences, P.O. Box 12233, MD EC-32, Research Triangle Park, NC; fax: 919-316-4511).

Journal Article↗
PubMed2003

NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of 2-Bromopropane (2-BP).

The National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (CERHR) conducted an evaluation of the potential for 2-bromopropane to cause adverse effects on reproduction and development in humans. 2-Bromopropane was selected for evaluation due to documented evidence of worker exposures and published evidence of reproductive toxicity in both rodents and humans. 2-Bromopropane may be used as an intermediate in the synthesis of pharmaceuticals, dyes, and other organic chemicals. In Asia, 2-bromopropane was also used as a replacement for chlorofluorocarbons and 1,1,1-trichloroethane, and is used as a solvent/cleaner for microelectronics. The results of this evaluation on 2-brompropane are published in a NTP-CERHR monograph which includes: 1) the NTP Brief, 2) the Expert Panel Report on the Reproductive and Developmental Toxicity of 2-Bromopropane, and 3) public comments received on the Expert Panel Report. As stated in the NTP Brief, the NTP reached the following conclusions regarding the possible effects of exposure to 2-bromopropane on human development and reproduction. No data were available on environmental exposure of the general public to 2-bromopropane. However, occupational exposure data indicate workplace exposures to 2-bromopropane range from </=0.004- 1.35 ppm. Conclusions were based on the available occupational exposure data and on studies in humans and laboratory animals. First, there is some concern for adverse reproductive effects when people are exposed to concentrations of 2-bromopropane at the high end of the occupational exposure range, and minimal concern at the low end of the exposure range. These conclusions are supported by toxicity in rats at 100 ppm exposures and adverse reproductive effects in occupationally exposed humans. Second, there is insufficient evidence to assess the developmental effects of 2-bromopropane exposure. These conclusions are based on occupational exposure data which do not account for dermal contact with 2-bromopropane. NTP-CERHR monographs are transmitted to federal and state agencies, interested parties, and the public and are available in electronic PDF format on the CERHR web site (http://cerhr.niehs.nih.gov) and in printed text or CD-ROM from the CERHR (National Institute of Environmental Health Sciences, P.O. Box 12233, MD EC-32, Research Triangle Park, NC; fax: 919-316-4511).

Journal Article↗
PubMed2003

NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Di-n-Butyl Phthalate (DBP).

TThe National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (CERHR) conducted an evaluation of the potential for di-n-butyl phthalate (DBP) to cause adverse effects on reproduction and development in humans. DBP is one of 7 phthalate chemicals evaluated by the NTP CERHR Phthalates Expert Panel. These phthalates were selected for evaluation because of high production volume, extent of human exposures, use in children's products, and/or published evidence of reproductive or developmental toxicity. Unlike many phthalates, DBP is not currently used as a plasticizer in polyvinyl chloride plastics. DBP is a component of latex adhesives and is used in cosmetics and other personal care products, as a plasticizer in cellulose plastics, and as a solvent for dyes. The results of this evaluation on DBP are published in a NTP-CERHR monograph which includes: 1) the NTP Brief, 2) the Expert Panel Report on the Reproductive and Developmental Toxicity of Di-n-Butyl Phthalate, and 3) public comments received on the Expert Panel Report. As stated in the NTP Brief, the NTP reached the following conclusions regarding the possible effects of exposure to DBP on human development and reproduction. First, although DBP could possibly affect human reproduction and development if exposures are sufficiently high, the NTP concludes that there is negligible concern for reproductive toxicity in exposed adults. Second, the NTP concludes that there is minimal concern for developmental effects when pregnant women are exposed to DBP levels estimated by the panel (2-10 mug/kg body weight/day). There is no direct evidence that exposure of people to DBP adversely affects reproduction or development, but studies reviewed by the expert panel show that oral exposure to high doses of DBP (>/=100 mg/kg body weight/day) may adversely affect the prenatal and early postnatal development in rodents. Finally, based on exposure estimates in women of reproductive age, the NTP concludes that there is some concern for DBP causing adverse effects to human development, particularly development of the male reproductive system. NTP-CERHR monographs are transmitted to federal and state agencies, interested parties, and the public and are available electronically in PDF format on the CERHR web site (http://cerhr.niehs.nih.gov) and in printed text or CD-ROM from the CERHR (National Institute of Environmental Health Sciences, P.O. Box 12233, MD EC-32, Research Triangle Park, NC; fax: 919-316-4511).

Journal Article↗
PubMed2003

NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Butyl Benzyl Phthalate (BBP).

The National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (CERHR) conducted an evaluation of the potential for butyl benzyl phthalate (BBP) to cause adverse effects on reproduction and development in humans. BBP is one of 7 phthalate chemicals evaluated by the NTP CERHR Phthalates Expert Panel. These phthalates were selected for evaluation because of high production volume, extent of human exposures, use in children's products, and/or published evidence of reproductive or developmental toxicity. BBP is used in the production of vinyl tiles and polyvinyl chloride (PVC) to make products such as food conveyor belts, carpet tile, tarps, artificial leather, automotive trim, and traffic cones. The results of this evaluation on BBP are published in a NTP-CERHR monograph which includes: 1) the NTP Brief, 2) the Expert Panel Report on the Reproductive and Developmental Toxicity of Butyl Benzyl Phthalate, and 3) public comments received on the Expert Panel Report. As stated in the NTP Brief, the NTP reached the following conclusions regarding the possible effects of exposure to BBP on human development and reproduction. First, the NTP concludes there is negligible concern for adverse reproductive effects in exposed men. Data are insufficient to reach a conclusion on possible eproductive effects in exposed women. There is no direct evidence that exposure of people to BBP adversely affects reproduction or development, but studies reviewed by the expert panel show that oral exposure of laboratory animals to high doses (>/=1000 mg/kg body weight/day) of BBP can adversely affect development, including development of the male reproductive tract. Second, the NTP concludes that there is minimal concern for developmental effects in fetuses and children. Evidence showed adverse reproductive effects in rats at doses of 100 mg/kg body weight/day, but not at 20 mg/kg/day. Exposure estimates for women of reproductive age were estimated to be 7.8 mug/kg body weight/day. Therefore, this estimated exposure is at least 2,500-to 25,000- fold lower than the toxic dose in rats. NTP-CERHR monographs are transmitted to federal and state agencies, interested parties, and the public and are available in electronic PDF format on the CERHR web site (http://cerhr.niehs.nih.gov) and in printed text or CD-ROM from the CERHR (National Institute of Environmental Health Sciences, P.O. Box 12233, MD EC-32, Research Triangle Park, NC; fax: 919-316-4511).

Journal Article↗
PubMed2002

Toxicology and carcinogenesis studies of p-nitrotoluene (CAS no. 99-99-0) in F344/N rats and B6C3F(1) mice (feed studies).

UNLABELLED: p-Nitrotoluene is used to synthesize agricultural and rubber chemicals, azo and sulfur dyes, and dyes for cotton, wool, silk, leather, and paper. p-Nitrotoluene was nominated by the National Institute for Occupational Safety and Health and the NTP for study based on its considerable human exposure as well as the absence of long-term studies of its carcinogenicity in rodents. Male and female F344/N rats and B6C3F1 mice were exposed to p-nitrotoluene (greater than 99% pure) in feed for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, L5178Y mouse lymphoma cells, cultured Chinese hamster ovary cells, and rat and mouse bone marrow cells. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were fed diets containing 0, 1,250, 2,500, or 5,000 ppm p-nitrotoluene (equivalent to average daily doses of approximately 55, 110, or 240 mg p-nitrotoluene/kg body weight to males and 60, 125, or 265 mg/kg to females) for 105 or 106 weeks. Survival, Body Weights, and Feed Consumption: Survival of all exposed groups of rats was similar to that of the control groups. Mean body weights of 5,000 ppm male and 2,500 and 5,000 ppm female rats were less than those of the controls during most of the study; mean body weights of 1,250 ppm females were less during the second year of the study. Feed consumption by 5,000 ppm females was less than that by the controls during year 2 of the study. Biomarkers of Exposure: Two urinary metabolites were followed during the study as biomarkers of exposure. The ratios of p-nitrobenzoic acid to creatinine and of p-acetamidobenzoic acid to creatinine determined at 2 weeks and at 3, 12, and 18 months were linearly related to exposure concentration in males and females. Pathology Findings: The incidence of clitoral gland adenoma or carcinoma (combined) was significantly greater in 2,500 ppm females than that in the controls and exceeded the historical control ranges. The incidence of clitoral gland neoplasms was not increased in 5,000 ppm females, possibly because of the lower body weights in this group. The incidences of subcutaneous fibroma and of subcutaneous fibroma or fibrosarcoma (combined) in 2,500 ppm male rats were significantly increased and exceeded the historical control ranges. The incidences of several nonneoplastic kidney lesions were significantly increased in exposed groups of rats, and the severities of these lesions generally increased with increasing exposure concentration. In the spleen, incidences of hematopoietic cell proliferation and pigmentation were significantly increased in the 2,500 and 5,000 ppm groups. Significantly increased incidences of various types of altered cell foci in the liver of males and females were associated with exposure. Incidences of germinal epithelial atrophy of the testis in 5,000 ppm males and endometrial cystic hyperplasia of the uterus in 2,500 and 5,000 ppm females were significantly increased. The incidences of mononuclear cell leukemia were significantly decreased in all exposed groups except 1,250 ppm females. The incidence of interstitial cell adenoma of the testis in 5,000 ppm males was significantly decreased. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were fed diets containing 0, 1,250, 2,500, or 5,000 ppm p-nitrotoluene (equivalent to average daily doses of approximately 170, 345, or 690 mg/kg to males and 155, 315, or 660 mg/kg to females) for 105 or 106 weeks. Survival, Body Weights, and Feed Consumption: Survival of all exposed groups of male and female mice was similar to that of the control groups. Mean body weights of 5,000 ppm males and females were less than those of the control groups during most of the study. Mean body weights of 2,500 ppm males were less than those of the controls after week 92. Feed consumption by all exposed groups of mice was similar to that by the control groups. Pathology Findings: The incidence of alveolar/bronchiolar adenoma or carcinoma (combined) was significantly greater in 5,000 ppm male mice than in the controls, as was the incidence of alveolar epithelial hyperplasia in this group. The incidences of alveolar epithelial bronchiolization were significantly increased in all exposed groups of males and females. GENETIC TOXICOLOGY: p-Nitrotoluene was not mutagenic in any of several strains of S. typhimurium, with or without metabolic activation enzymes (S9). A positive response to p-nitrotoluene was observed in the L5178Y mouse lymphoma cell assay in trials with S9. Significantly increased sister chromatid exchange frequencies were observed in cultured Chinese hamster ovary cells treated with p-nitrotoluene with and without S9. Chromosomal aberrations were also induced in Chinese hamster ovary cells treated with p-nitrotoluene in the presence of S9; no increased aberrations were seen without S9. p-Nitrotoluene did not induce a significant reproducible increase in the frequency of micronuclei in bone marrow polychromatic erythrocytes of male rats or male mice when administered by intraperitoneal injection. CONCLUSIONS: Under the conditions of these 2-year feed studies there was equivocal evidence of carcinogenic activity* of p-nitrotoluene in male F344/N rats based on increased incidences of subcutaneous skin neoplasms. There was some evidence of carcinogenic activity of p-nitrotoluene in female F344/N rats based on increased incidences of clitoral gland neoplasms. There was equivocal evidence those of the control groups during most of the study. Mean body weights of 2,500 ppm males were less than those of the controls after week 92. Feed consumption by all exposed groups of mice was similar to that by the control groups. Pathology Findings: The incidence of alveolar/bronchiolar adenoma or carcinoma (combined) was significantly greater in 5,000 ppm male mice than in the controls, as was the incidence of alveolar epithelial hyperplasia in this group. The incidences of alveolar epithelial bronchiolization were significantly increased in all exposed groups of males and females. GENETIC TOXICOLOGY: p-Nitrotoluene was not mutagenic in any of several strains of S. typhimurium, with or without metabolic activation enzymes (S9). A positive response to p-nitrotoluene was observed in the L5178Y mouse lymphoma cell assay in trials with S9. Significantly increased sister chromatid exchange frequencies were observed in cultured Chinese hamster ovary cells treated with p-nitrotoluene with and without S9. Chromosomal aberrations were also induced in Chinese hamster ovary cells treated with p-nitrotoluene in the presence of S9; no increased aberrations were seen without S9. p-Nitrotoluene did not induce a significant reproducible increase in the frequency of micronuclei in bone marrow polychromatic erythrocytes of male rats or male mice when administered by intraperitoneal injection. CONCLUSIONS: Under the conditions of these 2-year feed studies there was equivocal evidence of carcinogenic activity of p-nitrotoluene in male F344/N rats based on increased incidences of subcutaneous skin neoplasms. There was some evidence of carcinogenic activity of p-nitrotoluene in female F344/N rats based on increased incidences of clitoral gland neoplasms. There was equivocal evidence in male and female rats, testis in male rats, and lung in male and female mice. Decreased incidences of mononuclear cell leukemia in male and female rats and testicular interstitial cell adenoma in male rats were attributed to exposure to p-nitrotoluene.

Administration, Oral↗
PubMed2002

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

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

Animals↗