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National Toxicology Program

Publications and source records attributed to National Toxicology Program.

At least 469 records · Page 26Linked to original sources
PubMed1986

NTP Toxicology and Carcinogenesis Studies of Chlorinated Paraffins (C23, 43% Chlorine) (CAS No. 108171-27-3) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Toxicology and carcinogenesis studies of chlorinated paraffins (C23, 43% chlorine), an extreme-pressure lubricant and flame retardant, were conducted by administering the chemical in corn oil by gavage to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex, 5 days per week for 103 weeks. Additional groups of 10 rats per sex and dose were examined at 6 and at 12 months. Male rats received doses of 0, 1,875, or 3,750 mg/kg body weight; female rats were given 0, 100, 300, or 900 mg/kg. Male and female mice received 0, 2,500, or 5,000 mg/kg. Doses selected for the 2-year studies were based on the results from 13-week studies in which rats of each sex received 0 to 3,750 mg/kg, and mice of each sex, 0 to 7,500 mg/kg. No toxicity of chlorinated paraffins (C23, 43% chlorine) was observed in male rats or in male or female mice in the 13-week studies. A dose-related inflammation of the liver was observed in female rats in the 13-week studies and in male and female rats in the 13-week studies and in male and female rats at 6 and 12 months in the 2-year studies. Chlorinated paraffins (C23, 43% chlorine) administration did not influence mean body weights of rats during the 2-year studies, but both male and female low dose mice gained less weight than did vehicle controls or the high dose groups. Survival of dosed and vehicle control groups was similar for each sex and species (male rats: vehicle control, 30/50; low dose, 32/50; high dose, 27/50; female rats: 34/50; 30/50; 33/50; 31/50; male mice: 29/50; 36/50; 28/50; female mice: 21/50; 22/50; 20/50). For female mice, 60%-70% of the early deaths in each group were attributed to utero-ovarian infection. The lower survival for female mice may have decreased the sensitivity of this study to detect a carcinogenic effect. Pheochromocytomas of the adrenal gland medulla occurred with an increased incidence in female rats exposed to chlorinated paraffins (C23, 43% chlorine) (vehicle control, 1/50; low dose, 4/50; mid dose, 6/50; high dose, 7/50). However, adrenal gland medullary hyperplasia was not increased (6/50; 3/50; 1/50; 6/50). Malignant lymphomas were increased in dosed male mice (6/50; 12/50; 16/50). High dose female mice showed a marginal increase in the incidence of hepatocellular carcinomas (1/50; 1/49; 6/50) and in the incidence of adenomas or carcinomas (combined) (4/50; 3/49; 10/50). The primary nonneoplastic lesion associated with chlorinated paraffins (C23, 43% chlorine) administration was a diffuse lymphohistiocytic inflammation in the liver and in the pancreatic and mesenteric lymph nodes of male and female rats. Splenic congestion was a secondary effect. These lesions occurred earlier and at lower doses in female rats than in male rats. No significant nonneoplastic lesions were considered compound related in mice. Chlorinated paraffins (C23, 43% chlorine) was not mutagenic in strains TA100, TA1535, TA97, or TA98 of Salmonella typhimurium in the presence or absence of Aroclor 1254-induced male Sprague-Dawley rat or male Syrian hamster liver S9 when assayed according to the preincubation protocol. An audit of the experimental data was conducted for these 2-year studies of chlorinated paraffins (C23, 43% chlorine). No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenicity of chlorinated paraffins (C23, 43% chlorine) for male F344/N rats given 1,875 or 3,750 mg/kg per day. There was equivocal evidence of carcinogenicity of chlorinated paraffins (C23, 43% chlorine) for female F344/N rats as shown by an increased incidence of adrenal gland medullary pheochromocytomas. There was clear evidence of carcinogenicity of chlorinated paraffins (C23, 43% chlorine) for male B6C3F1 mice as shown by an increase in the incidence of malignant lymphomas. There was equivocal evidence of carcinogenicity of chlorinated paraffins (C23, 43% chlorine) for female B6C3F1 mice as shown by a marginal increase in the incidence of hepatocellular neoplasms. *The Chemical Abstract Service Seal increase in the incidence of hepatocellular neoplasms. *The Chemical Abstract Service Service (CAS) number that appeared on this technical report at the time of publication (63449-39-8) reflects the generic CAS number for chlorinated paraffins. This number has been replaced in the NTP Chemtrack chemical tracking system with the more appropriate number.

Journal Article↗
PubMed1986

NTP Toxicology and Carcinogenesis Studies of 4-Vinylcyclohexene (CAS No. 100-40-3) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Toxicology and carcinogenesis studies of 4-vinylcyclohexene (greater than 98% pure), a dimer of 1,3-butadiene present in the off-gasses from tire curing, were conducted by administering the chemical in corn oil by gavage 5 days per week at doses of 0, 200, or 400 mg/kg body weight to groups of 50 F344/N rats and B6C3F1 mice of each sex for 103 weeks. Doses selected for the 2-year studies were based on survival, body weight gains, and histopathologic effects observed during the 14-day and 13 week studies. All rats and most mice in the 14-day studies died when administered doses greater than or equal to 1,250 mg/kg, although no compound-related gross or histopathologic effects were observed. Final body weights were reduced in the 13-week studies in male rats receiving doses greater than or equal to 400 mg/kg of 4-vinylcyclohexene, in female rats receiving 800 mg/kg, and in female mice receiving 600 mg/kg. Extensive mortality was observed only in mice dosed at 1,200 mg/kg. Compound-related histopathologic effects in the 13-week studies included hyaline droplet degeneration of the proximal convoluted tubules of the kidney in dosed male rats, the severity of which was dose related, and a reduction in the number of primary follicles and mature graafian follicles in the ovaries of female mice receiving 1,200 mg/kg of 4-vinylcyclohexene. No compound-related gross or histopathologic effects were evident in dosed female rats or male mice in the 13-week studies. Many dosed rats died early in the 2-year studies (male: vehicle control, 17/50; low dose, 37/50; high dose, 45/50; female: vehicle control, 10/50; low dose, 22/50; high dose, 36/50; P<0.001 for all groups except low dose female rats, for which P=0.022). The poor survival of dosed male and female rats reduced the sensitivity of the studies for detecting the possible carcinogenic effects of 4-vinylcyclohexene. Mean body weights of dosed rats were comparable to those of their respective vehicle controls, except for high dose males late in the study. Survival of high dose mice of each sex was lower (P<0.001) than that of the vehicle controls, whereas survival of low dose mice of each sex was comparable to that of the vehicle controls. Mean body weights of high dose mice of each sex were generally lower than those of the vehicle controls throughout most of the 2-year studies. Administration of 4-vinylcyclohexene to F344/N rats by gavage for 2 years was associated with a slightly increased incidence of epithelial hyperplasia of the forestomach (1/50; 3/50; 5/47) and squamous cell papillomas or carcinomas (combined) of the skin in high dose males (0/50; 1/50; 4/50). Low dose female rats, whose survival was more similar to that of the vehicle controls, had a marginally increased incidence of adenomas or squamous cell carcinomas (combined) of the clitoral gland (1/50; 5/50; 0/49). In B6C3F1 mice, administration of 4-vinylcyclohexene for two years by gavage was associated with mild, acute inflammatory lesions and epithelial hyperplasia of theforestomach, especially in males (0/47; 7/50; 7/46), and with an increased incidence of a number of other nonneoplastic lesions, including lung congestion in high dose males and females, splenic red pulp atrophy in high dose males, congestion of the adrenal gland in high dose females, and cytologic alteration of the adrenal cortex in low dose and high dose females. The incidences of uncommon ovarian neoplasms were markedly increased (P<0.01) in both groups of dosed female mice (mixed tumor, benign: 0/49; 25/48, 52%; 11/47, 23%; granulosa cell tumor or carcinoma [combined]: 1/49, 2%; 10/48, 21%; 13/47, 28%). In addition, a slight increase in the incidence of adrenal gland adenomas in high dose females was observed (0/50; 3/49, 6%; 4/48, 8%). The extensive mortality seen in the high dose male mice confounded interpretation of the increased incidences of malignant lymphomas and alveolar/bronchiolar adenomas or carcinomas (combined) of the lung seen in these animals surviving to the end of the study (malignant lymphomas: 3/37, 8%; 5/39, 13%; 4/7, 57d of the study (malignant lymphomas: 3/37, 8&percnt;; 5/39, 13&percnt;; 4/7, 57&percnt;; alveolar/bronchiolar adenomas or carcinomas [combined]: 3/37, 8&percnt;; 9/39, 23&percnt;; 3/7, 43&percnt;). 4-Vinylcyclohexene was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, or TA98 in the presence or absence of Aroclor 1254-induced male Sprague-Dawley rat or male Syrian hamster liver S9 when tested according to the preincubational protocol. However, several of its metabolites, including 4-vinylcyclohexene diepoxide, have been shown to be mutagenic in Salmonella and/or induce chromosomal damage in vitro. An audit of the experimental data was conducted for these 2-year carcinogenesis studies on 4-vinylcyclohexene. No data discrepancies were found that influenced the final interpretations. 4-Vinylcyclohexene was administered by gavage in corn oil to F344/N rats and B6C3F1 mice of each sex at doses of 200 or 400 mg/kg for 103 weeks. Under these conditions, the 2-year gavage studies of 4-vinylcyclohexene in male and female rats and male mice were considered inadequate studies of carcinogenicity because of extensive and early mortality at the high dose or at both doses and the lack of conclusive evidence of a carcinogenic effect. There was clear evidence of carcinogenicity of 4-vinylcyclohexene for female mice, as shown by markedly increased incidences of uncommon ovarian neoplasms at both doses. In addition, the increased incidence of adrenal gland adenomas in high dose female mice may have been related to the administration of 4-vinylcyclohexene. Synonym: 4-ethenylcyclohexene

Journal Article↗
PubMed1986

NTP Toxicology and Carcinogenesis Studies of Chlorpheniramine Maleate (CAS No. 113-92-8) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Toxicology and carcinogenesis studies of chlorpheniramine maleate (99% pure), a widely used antihistaminic drug in human and veterinary medicine, were conducted by administering this chemical in deionized water by gavage to groups of 50 male and 50 female F344/N rats and B6C3F1 mice, 5 days per week for 103 weeks. The doses used were: male rats-- 0, 15, or 30 mg/kg; female rats-- 0, 30, or 60 mg/kg; male mice-- 0, 25, or 50 mg/kg; female mice-- 0, 100, or 200 mg/kg. The selection of these doses was based largely on data from 14-day or 16-day studies and 13-week studies in which reduced body weight gain and reduced survival occurred at higher doses. Doses used in the 2-week studies ranged from 40 to 640 mg/kg in rats and 25 to 800 mg/kg in mice; in the 13-week studies, doses ranged from 3.75 to 60 mg/kg in rats and 12.5 to 200 mg/kg in mice. The recommended human adult daily oral dose of chlorpheniramine maleate is up to 0.32 mg/kg. Doses originally selected for male mice in the 2-year study were 0, 100, or 200 mg/kg; however, because of poor survival, that study was stopped and a new study was started at doses of 0, 25, or 50 mg/kg. At the termination of the study (week 104), survival of high dose female rats (6/50) and high dose male mice (15/50) was lower than that of the vehicle controls (29/50 and 39/50, respectively). Survival of all other dosed groups was comparable to that of respective vehicle control groups. Mean body weights of dosed rats were about 10%-15% (male) or about 10%-25% (female) lower than those of vehicle controls; mean body weights of female mice were generally 20%-35% lower than those of vehicle controls. No compound-related gross or microscopic pathologic effects were observed in either species in the 16-day or 13-week studies. Hyperactivity and hyperexcitability associated with dosing were frequently noted in the 13-week and 2-year studies. There were no significant positive trends or increases in the incidences of neoplasms in either male or female rats dosed with chlorpheniramine maleate for 103 weeks. Marginal increases in the incidences of adrenal gland capsule adenomas in male mice (vehicle control, 2/50; low dose, 7/49; high dose, 4/49) were not considered to be compound related, since there was not a corresponding increase in the incidence of adrenal gland capsule hyperplasia (46/50; 33/49; 22/49). A positive trend was seen for subcutaneous tissue tumors in male mice (4/50; 5/49; 8/50); this marginal effect was not considered to be compound related. The incidences of thyroid gland follicular cell cysts (2/48; 10/49; 13/47), thyroid gland follicular cell hyperplasia (3/48; 29/49; 36/47), and thyroid gland follicular cell adenomas (0/48; 4/49; 2/47) were greater in dosed female mice than in vehicle controls. This finding is toxicologically important,since thyroid gland neoplasms are uncommon in mice and are often preceded by hyperplasia of the follicular epithelium. The major route of excretion of chlorpheniramine or its metabolites is in the urine. In male F344 rats orally administered 14C-chlorpheniramine maleate at doses of 2 or 20 mg/kg, there was essentially no difference in the percentage of urinary or fecal excretion of radioactivity between these dose levels. Chlorpheniramine maleate was not mutagenic to Salmonella strains TA98, TA100, TA1535, or T1537 in the presence or absence of S9 metabolic activation systems prepared from the liver of Aroclor 1254-treated male Sprague-Dawley rats or male Syrian hamsters. Chlorpheniramine maleate did not induce forward mutations at the TK locus of L5178Y mouse lymphoma cells with or without metabolic activation. In Chinese hamster ovary cells in culture, chlorpheniramine maleate induced a weak but reproducible increase in sister-chromatid exchanges in the absence of exogenous metabolic activation. Chromosomal aberrations were induced at the highest dose tested but only in the presence of S9 from Aroclor 1254-induced Sprague-Dawley male rat liver. An audit of the experimental data was conducted for these 2-year carcinogenesis studies on chlorpher these 2-year carcinogenesis studies on chlorpheniramine maleate. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenicity for F344/N rats or B6C3F1 mice of either sex administered chlorpheniramine maleate in deionized water, 5 days per week for 2 years. Due to high mortality in high dose female rats and high dose male mice, the sensitivity of these groups to detect a carcinogenic response was reduced. Chlorpheniramine maleate had a proliferative effect in the thyroid gland of female mice, as shown by the increased incidences of follicular cell cysts and hyperplasia in both low dose and high dose groups. Synonyms: 2-p-chloro-a-(2-dimethylaminoethyl) benzyl]pyridine maleate; 2-Pyridinepropanamine; gamma-[4-chlorophenyl]-N,N-dimethyl-[z]-2-butenedioate Trade Names: Allerclor; Allergisan; Antagonate; Chlormene; Chlorprophenpyridamine maleate; Chlor-Trimeton; Chlor-Tripolon; Chloropiril; C-Meton; Histadur; Histaspan; Lorphen; M.P. Chlorcaps T.D.; Piriton; Pyridamal-100; Teldrin

Journal Article↗
PubMed1986

NTP Toxicology and Carcinogenesis Studies of Dimethylvinyl Chloride (1-Chloro-2-Methylpropene) (CAS No. 513-37-1) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Dimethylvinyl chloride is a clear colorless liquid, which, because of its volatility and flammability at room temperature, is a significant fire hazard. It has a boiling point of 68.1 degrees C (155 degrees F) and a density at 20 degrees C of 0.919 g/ml. Dimethylvinyl chloride is a byproduct in the production of 3-chloro-2-methylpropene by the chlorination of isobutene. It is not known to be produced in the United States for other than laboratory purposes. This chemical was nominated for toxicologic studies because of its reported presence in ambient air in the Baltimore area and was selected for toxicologic characterization because of its structural similarity to the known animal and human carcinogen, vinyl chloride monomer. Toxicology and carcinogenesis studies of dimethylvinyl chloride (96%-98% pure), a structural analog of vinyl chloride monomer, a known human carcinogen, by administered dimethylvinyl chloride in corn oil by gavage to groups of 50 male and 50 female F344/N rats and B6C3F1 mice at doses of 0, 100, or 200 mg/kg body weight 5 days per week for 102 or 103 weeks. The selection of these doses was based on results of 13-week studies, which included depression of body weight at doses of 500 mg/kg or above in rats as well as histopathologic changes intestinal epithelium, bone marrow, hepatocytes, and the testes at doses of 250 mg/kg and above; doses in mice were selected on the basis of histopathologic changes in lymphopoietic cells, liver, pancreatic islets, ovary, testis, and spleen, with changes being most prominent at doses of 500 mg/kg and above. In the 2-year studies, body weights of rats and mice given 100 mg/kg were comparable to those of the vehicle controls except for the last few weeks in mice when body weights were markedly lower than those for the vehicle controls. At 200 mg/kg, the mean body weights of rats and mice were progressively decreased relative to those of vehicle controls, with the significant departure from vehicle controls occurring somewhat earlier in males than in females. Survival of vehicle control rats and mice was comparable to historical values; however, survival of dosed male and female rats was significantly lower than that of vehicle controls, with the incidence of mortality being more severe at the high dose than at the low dose. There were no survivors in the high dose group of male rats after week 85 or in the high dose group of female rats after week 97. Survival was significantly lower among dosed male and female mice compared with vehicle controls. In the absence of toxicological findings that would explain the early deaths, it is assumed that the high incidence of tumors and chemical-related toxicity contributed to the decreased survival of dosed rats and mice. In rats, the severity and incidence of nonneoplastic lesions were minimal; these lesions included necrosis of the duodenum and epithelial hyperplasia at the sites of tumor formation--the nasal cavity, esophagus, and forestomach. In mice, the severity of nonneoplastic lesions was also minimal; the lesions included necrosis of the liver, bone marrow granulocytic hyperplasia, and inflammation of the nasal cavity (small number, females only.) Several types of neoplastic lesions occurred with significantly increased incidences in dosed animals as shown in the following table (see page 11 of Technical Report). Among rats, these lesions included malignant epithelial tumors of the nasal cavity and squamous cell tumors of the oral cavity, esophagus, and forestomach in males and females. The increased number of fibroadenomas of the mammary gland in female rats may have been related to dimethylvinyl chloride administration. The lack of a clear dose-response relationship for certain tumors in rats is considered to be related to the increased number of early deaths observed in the high dose groups. Among dosed mice, there were significantly increased incidences of squamous cell carcinomas of the forestomach (both sexes), squamous cell papillomas of the forestomach (males), and squamous cell carcinomas of the preputial gla preputial gland (males). The increased incidence of papillary adenomas of the harderian gland and alveolar/bronchiolar adenomas or carcinomas in female mice may have been related to administration of dimethylvinyl chloride. Limited metabolism studies of 14C-labeled dimethylvinyl chloride were conducted in male F344/N rats and B6C3F1 mice. Single doses of 150 mg/kg were administered to rats for 1, 2, or 4 consecutive days. About 25&percnt; of the administered doses was exhaled as carbon dioxide; this amount was independent of the number of doses administered. Another 25&percnt;-35&percnt; of the administered dose was exhaled; 96&percnt; of this parent was material. Approximately 35&percnt; and 6&percnt; were excreted in the urine and feces, respectively. The elimination half-life of radioactive label was 3-4 days for the liver and kidney, the two organs containing the greatest amounts of the administered dose. In mice, a much smaller fraction of the dose was exhaled and a larger proportion was excreted in urine compared with rats. Dimethylvinyl chloride was not mutagenic in four strains ofSalmonella typhimurium with or without metabolic activation, but it was mutagenic in the mouse lymphoma L5178Y/TK&plusmn; assay in the absence of metabolic activation. Sister-chromatid exchanges were induced in Chinese hamster ovary cells with and without metabolic activation, but there was no increase in chromosomal aberrations. When fed to Drosophila, dimethylvinyl chloride induced significant increases in the frequencies of both sex-linked recessive lethal mutations and reciprocal translocations. Studies of the immunotoxicity of dimethylvinyl chloride were conducted in which female B6C3F1 mice received daily oral doses of 0, 50, 100, 200, or 400 mg dimethylvinyl chloride per kilogram body weight. Compound-related increases in susceptibility to bacterial infection and decreases in macrophage cytostasis were observed at all doses. At the highest dose, the decreased resistance to bacterial and viral challenge could be related to alterations in specific immune function. However, the increased mortality in rats and mice in the 2-year studies was not relatable to infectious processes. An audit of the experimental data was conducted for these2-year toxicology and carcinogenesis studies on dimethylvinyl chloride. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenicity of dimethylvinyl chloride for both sexes of F344/N rats and B6C3F1 mice. This was based on increased incidences of neoplasms of the nasal cavity, oral cavity, esophagus, and forestomach of male and female F344/N rats. B6C3F1 mice showed increased incidences of squamous cell neoplasms of the forestomach in males and females and squamous cell carcinomas of the preputial gland in males. Synonym: 1-chloro-2-methylpropene

Journal Article↗
PubMed1986

NTP Toxicology and Carcinogenesis Studies of Methyl Methacrylate (CAS No. 80-62-6) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

Toxicology and carcinogenesis studies of methyl methacrylate, a liquid chemical intermediate used in the plastics industry in the manufacture of plexiglass and other acrylic products, were conducted by exposing groups of F344/N rats and B6C3F1 mice by inhalation for 14 weeks and 2 years. In the 14-week studies, groups of 10 male and 10 female rats and mice were exposed to methyl methacrylate at concentrations of up to 5,000 ppm. All male and female rats and eight male and eight female mice exposed at 5,000 ppm died, one male and nine female rats and four male and no female mice exposed at 3,000 ppm died, and one male and three female rats and two male and one female mouse exposed at 2,000 ppm died; all rats and mice exposed at 500 or 1,000 ppm survived. Compared with the controls, the body weights of the exposed male and female rats and mice were lower. Compound-related lesions included inflammation associated with necrosis and loss of olfactory epithelium in the nasal turbinates in both male and female rats; malacia and gliosis in female rats; inflammation of the nasal turbinates and nasal epithelium metaplasia in both male and female mice; and renal cortical necrosis, renal cortical tubular degeneration, renal focal mineralization, and liver necrosis in male mice. Based on these results, 2-year inhalation toxicology and carcinogenesis studies were conducted in which groups of 50 male rats were exposed to methyl methacrylate at 0, 500, or 1,000 ppm; female rats at 0, 250, or 500 ppm; and male and female mice at 0, 500, or 1,000 ppm. In the 2-year studies, the body weights of the low dose and high dose male and female rats were within 10% of those of the controls. There was no difference in survival between the dosed male and female rats and the controls. Incidences of inflammation of the nasal cavity and degeneration of the olfactory sensory epithelium were greater in the dosed male and female rats than in the controls, with lesions seen in virtually all high dose animals. An increased incidence of mononuclear cell leukemia was observed in female rats exposed to methyl methacrylate at 500 ppm compared with the controls (control, 11/50; 250 ppm, 13/50; 500 ppm, 20/50). This increase was not significant by life table tests, the method of analysis most appropriate for this fatal neoplasm. The mean body weights of dosed male and female mice were 5%-8% lower than those of the controls at the end of the 2-year studies. However, during most of the second year of the studies, body weights of dosed male mice and high dose female mice were 10%-18% lower than those of the controls. Survival rates of the dosed and control mice were similar. Incidences of inflammation and epithelial hyperplasia of the nasal cavity and degeneration of the olfactory sensory epithelium were significantly greater in all dosed groups of male and female mice compared with those of the controls. Compound-related neoplastic lesions were not found in the dosed mice. Significant dose-related decreases were observed in the incidences of pituitary gland and preputial gland tumors in male rats, alveolar/bronchiolar adenomas or carcinomas (combined) in male mice, hepatocellular adenomas in both male and female mice, and pituitary gland adenomas or adenocarcinomas (combined) and uterine adenocarcinomas in female mice. Methyl methacrylate was not mutagenic in strains TA100, TA1535, TA97, or TA98 of Salmonella typhimurium in the presence or absence of male rat or hamster liver S9 when assayed by a preincubational protocol but gave a positive response in L5178Y/TK+/- mouse lymphoma cells in the presence or absence of male rat liver S9. In cultured Chinese hamster ovary cells, methyl methacrylate produced a reproducible, dose-related increase in the frequency of sister-chromatid exchanges, both with and without rat liver S9. A slight, dose-related increase in chromosomal aberrations was also induced in cultured Chinese hamster ovary cells in the absence of S9; in the presence of S9, an increase in the frequency of aberrations was seen only at the highest, near-lethalas seen only at the highest, near-lethal dose of 5 mg/ml. An audit of the experimental data was conducted for the 2-year carcinogenesis studies on methyl methacrylate. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year inhalation studies, there was no evidence of carcinogenicity of methyl methacrylate for male F344/N rats exposed at 500 or 1,000 ppm, for female F344/N rats exposed at 250 or 500 ppm, or for male and female B6C3F1 mice exposed at 500 or 1,000 ppm. Inhalation of methyl methacrylate was associated with inflammation of the nasal cavity and degeneration of the olfactory sensory epithelium in male and female rats and mice; epithelial hyperplasia of the nasal cavity was also observed in exposed mice. Synonyms: acrylic acid, 2-methyl, methyl ester; methacrylic acid, methyl ester; methyl a-methylacrylate; methyl methylacrylate; methyl-2-methylpropenoate; methyl-2-methyl-2-propenoate; 2-methyl-2-propenoic acid methyl ester; MME

Journal Article↗
PubMed1985

NTP Toxicology and Carcinogenesis Studies of Propylene (CAS No. 115-07-1) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

Propylene is used as a starting material in the production of polypropylene plastics and various other chemicals, including acrylonitrile, isopropyl alcohol, propylene oxide, butyraldehyde, cumene, dodecane, nonene, and allyl chloride. The major derivatives are polypropylene (25%), acrylonitrile (15%), isopropyl alcohol (10%), and propylene oxide (10%). It is also a valuable feed-stock chemical for the production of gasoline. Other miscellaneous applications include use as a starting material for polymerization reactions to form vinyl chloride copolymers and low-molecular-weight homopolymers that are used as additives in lubricating oils and in the manufacture of hydroquinone. The chemical is also used as an aerosol propellant or component. The major end uses of propylene are in the production of fabricated plastics (50%) and fibers (15%). Toxicology and carcinogenesis studies of propylene (greater than 99% pure) were conducted by exposing groups of 50 F344/N rats and 49 or 50 B6C3F1 mice of each sex to propylene in air by inhalation at concentrations of 5,000 or 10,000 ppm, 6 hours per day, 5 days per week, for 103 weeks. Other groups of 50 rats and 50 mice of each sex in chambers received air only on the same schedule and served as chamber controls. The highest concentration of propylene that was considered safe for these studies was 10,000 ppm because of the risk of explosion that can occur at higher concentrations. The survival of exposed and control rats and mice was comparable. Throughout most of the studies, mean body weights of exposed male and female rats were slightly lower (0%-5%) than those of the controls, but the decrements were not concentration related. After week 59 of the study, mean body weights of 10,000-ppm male mice were usually slightly lower (5%) than those of the controls, whereas those in other exposed groups of male and female mice were generally comparable with those of the controls. No compound-related adverse clinical signs were observed in either species. An increased incidence of squamous metaplasia of the nasal cavity was observed in female rats exposed at the 5,000-ppm and 10,000-ppm concentrations (control, 0/49; low, 15/50; high, 6/50) and in male rats exposed at 5,000 ppm (2/50; 19/50; 7/50). Epithelial hyperplasia of the nasal cavity was increased in female rats exposed at the 10,000-ppm concentration (0/49; 4/50; 9/50); the incidences in male rats were 2/50, 2/50, and 5/50. Inflammation of the nasal cavity, characterized by an influx of lymphocytes, macrophages, and granulocytes into the submucosa and by granulocytes into the lumen, occurred at increased incidences in low concentration and high concentration male rats and in high concentration female rats. Chronic focal inflammation of the kidneys occurred at an increased incidence in low concentration and high concentration mice of each sex. Hemangiosarcomas were found in one low dose male mouse (liver), two high dose male mice (spleen), and three high dose female mice (subcutis, spleen, and uterus). Hemangiomas were found in one low dose and in one high dose female mouse (liver). Vascular tumors were not found in control mice of either sex. The low incidences of vascular tumors and their occurrence in a variety of organs suggest that they are not related to administration of propylene. The occurrence of uterine endometrial stromal polyps in female mice showed a positive trend (P<0.05; 0/47; 0/47; 3/48); the incidence in the 10,000-ppm group was not significantly greater than that in the concurrent control group, but the incidence was higher than the mean historical control rate (22/2,411, 0.9%) and was within the range (0%-6%) observed in studies throughout the Carcinogenesis Program. The occurrence of endometrial stromal polyps in three high concentration female mice was not considered to be clearly related to exposure to propylene. The incidence of male mice with alveolar/bronchiolar adenomas or carcinomas (combined) occurred with a negative trend (P<0.05; 16/50; 4/49; 7/50), and the reduced incidences in both exposed groups wegative trend (P<0.05; 16/50; 4/49; 7/50), and the reduced incidences in both exposed groups were less (P<0.05) than that in the control group. The control incidence of these tumors in an inhalation study conducted concurrently at the same laboratory was similar (15/50), suggesting a possible exposure-related decrease. The biologic significance of this decrease in male mice is difficult to assess; the incidences seen in these control and exposed animals are within the range of incidences (2&percnt;-34&percnt;; mean, 16.7&percnt;) observed in control male mice in other studies throughout the Carcinogenesis Program. An audit of the experimental data was conducted for these carcinogenesis studies on propylene. No data discrepancies were found that influenced the final interpretations. Under the conditions of these studies, there was no evidence of carcinogenicity in male and female F344/N rats or in male and female B6C3F1 mice exposed to propylene by inhalation at concentrations of 5,000 or 10,000 ppm for 103 weeks. In the nasal cavity, propylene induced squamous metaplasia of the respiratory epithelium in male and female rats and epithelial hyperplasia in female rats. Synonyms: propene; methylethylene; methylethene

Journal Article↗
PubMed1985

NTP Toxicology and Carcinogenesis Studies of HC Blue No. 1 (CAS No. 2784-94-3) in F344/N Rats and B6C3F1 Mice (Feed Studies).

Toxicology and carcinogenesis studies of HC Blue No. 1 (97% pure), a semipermanent hair dye, were conducted by administering the test chemical in feed for 103 weeks to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex. The dietary concentrations used were 0, 1,500, or 3,000 ppm for rats and male mice and 0, 3,000, or 6,000 ppm for female mice. These concentrations were selected on the basis of results from single-administration gavage studies and 14-day and 13-week feed studies. The survival of male and female rats and male mice was not affected by administration of HC Blue No. 1. Survival of high dose female mice was reduced (P<0.05); the early deaths in this group are believed to have been caused by hepatocellular carcinomas. Body weights of high dose rats and dosed mice were lower than those of the respective control groups; female rats and mice were more affected than were males. Administration of HC Blue No. 1 produced significant positive trends in the incidences of male rats with hepatocellular neoplastic nodules/carcinomas (neoplastic nodules: control, 0/49; low dose, 0/50; high dose, 3/50; neoplastic nodules/carcinomas: 1/49; 0/50; 6/50). In male and female mice, both doses of HC Blue No. 1 increased the incidences of hepatocellular carcinoma (male: 11/50; 20/50; 30/50; female: 1/50; 24/48; 47/49) and the low doses increased the incidences of hepatocellular adenomas (male: 4/50; 17/50; 10/50; female: 2/50; 11/48; 4/49). HC Blue No. 1 produced dose-related increases in the incidences of proliferative lesions of the lungs (adenomatous hyperplasia and alveolar/bronchiolar adenomas or carcinomas) in female rats (hyperplasia: 2/50; 5/49; 8/50; adenoma/carcinoma: 1/50; 3/49; 7/50). In male mice, HC Blue No. 1 at the 6,000-ppm dose increased the incidences of thyroid gland follicular cell hyperplasia and adenomas (hyperplasia: 3/47; 7/49; 14/50; adenoma: 0/47; 0/49; 5/50). HC Blue No. 1 was mutagenic in strains TA97, TA98, and TA100 of Salmonella typhimurium in the presence or absence of Aroclor-induced male Sprague-Dawley rat or Syrian hamster liver S9; HC Blue No. 1 was negative in strain TA1535. HC Blue No. 1 was mutagenic in the absence of activation in the L5178Y/TK+/- mouse lymphoma assay and induced unscheduled DNA synthesis in rat hepatocytes in vitro. An audit of the experimental data was conducted for these carcinogenesis studies on HC Blue No. 1. No data discrepancies were found that influenced the final interpretations. Under the conditions of these feed studies, there was equivocal evidence of carcinogenicity in male F344/N rats, since HC Blue No. 1 caused a marginal increase in the incidence of hepatocellular neoplastic nodules/carcinomas. For female F344/N rats, there was some evidence of carcinogenicity in that HC Blue No. 1 induced increased incidences of alveolar/bronchiolar neoplasms. There was clear evidence of carcinogenicity of HC Blue No. 1 for male and female B6C3F1 mice as shown by increased incidences of hepatocellular carcinomas. The incidences of follicular cell adenomas of the thyroid gland were also increased in male mice receiving HC Blue No. 1. Synonym: 2,2'((4-(methylamino)-3-nitrophenyl)imino)bis (ethanol)

Journal Article↗
PubMed1985

NTP Toxicology and Carcinogenesis Studies of Telone II(R) (Technical-Grade 1,3-Dichloropropene [CAS No. 542-75-6] Containing 1.0% Epichlorohydrin as a Stabilizer) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Toxicology and carcinogenesis studies of Telone II(R) (a soil fumigant containing approximately 89% cis- and trans-1,3-dichloropropene, 2.5% 1,2-dichloropropane, 1.5% of a trichloropropene isomer, and 1.0% epichlorohydrin) were conducted by administering the commercial-grade formulation in corn oil by gavage to groups of 52 male and 52 female F344/N rats at doses of 0, 25, or 50 mg/kg and to groups of 50 male and 50 female B6C3F1 mice at doses of 0, 50, or 100 mg/kg. Doses were administered three times per week for 104 weeks. Ancillary studies were conducted in which dose groups containing five male and five female rats were killed after receiving Telone II(R) for 9, 16, 21, 24, or 27 months. Mean body weights of high dose male rats were about 5% lower than those for the vehicle control and low dose male rats; no differences in body weights were observed among groups of female rats. Survival was comparable for the different groups of male and female rats. For male and female mice, the dosed groups initially weighed 6%-22% less than did the vehicle controls; the weight differential decreased to 5%-9% by the end of the studies. Twenty-five vehicle control male mice died during weeks 48-51 from suppurative inflammation of the heart (myocarditis). At the end of the studies, the survival of male mice was as follows: vehicle control, 8/50; low dose, 28/50; high dose 31/50. Survival of female mice was lower (P<0.05) in the high dose group than in the vehicle controls (46/50; 45/50; 36/50). The primary organs affected were the forestomach (rats and mice), urinary bladder (mice), lung (mice), and liver (rats). Compound-related nonneoplastic lesions included basal cell or epithelial hyperplasia of the forestomach (rats and mice), epithelial hyperplasia of the urinary bladder (mice), and kidney hydronephrosis (mice). Neoplastic lesions associated with administration of Telone II(R) included squamous cell papillomas of the forestomach (male rats: 1/52; 1/52; 9/52; female rats: 0/52; 2/52; 3/52; female mice: 0/50; 1/50; 2/50), squamous cell carcinomas of the forestomach (male rats: 0/52; 0/52; 4/52; female mice: 0/50; 0/50; 2/50), transitional cell carcinomas of the urinary bladder (female mice: 0/50; 8/50; 21/48), alveolar/bronchiolar adenomas (female mice: 0/50; 3/50; 8/50), and neoplastic nodules of the liver (male rats: 1/52; 6/52; 7/52). Although the study in male mice was considered inadequate due to the deaths at weeks 48-51 of 25/50 vehicle control animals, 2/50 of the high dose males had transitional cell carcinomas of the urinary bladder. Furthermore, increases were seen in the incidences of alveolar/bronchiolar neoplasms of the lung (1/50; 13/50; 12/50) and of squamous cell papillomas of the forestomach (0/50; 2/50; 3/50). These findings plus the finding of nonneoplastic lesions in two of these organs (basal cell or epithelial hyperplasia of the forestomach: 0/50; 0/50; 4/50; epithelial hyperplasia of the urinary bladder: 0/50; 9/50; 18/50) suggest that Telone II(R) may have been responsible for the development of these lesions in male mice. Development of lesions of the forestomach (basal cell hyperplasia and squamous cell papilloma) was observed to be time dependent. The results of the scheduled kills supported the findings of the carcinogenesis studies. When the results from the scheduled kills at all time points were pooled with those of the 24-month carcinogenesis studies, the incidences were as follows: basal cell or epithelial hyperplasia of the forestomach-- male rats: 3/77; 13/77; 31/77; female rats: 1/75; 5/77; 35/77; squamous cell papilloma of the forestomach-- male rats: 1/77; 1/77; 13/77; female rats: 0/75; 2/77; 8/77; neoplastic nodules of the liver--male rats: 1/77; 6/76; 8/77; female rats: 6/75; 8/77; 12/77. cis- and trans-1,3- Dichloropropane are the principle components (89%) in Telone II(R), but the 1.0% epichlorohydrin, a direct-acting mutagen and carcinogen added as a stabilizer, may have influenced the development of the forestomach lesions. 1,3-Dichloropropene was mutagenic in Salmonella typhimuriumnt of the forestomach lesions. 1,3-Dichloropropene was mutagenic in Salmonella typhimurium strains TA98, TA100, and TA1535 without metabolic activation and in TA100 and TA1535 with metabolic activation by Aroclor-induced male Sprague-Dawley rat and Syrian hamster liver S9. No mutagenic response was seen in TA1537. Sex-linked recessive lethal mutations were observed in Drosophila melanogaster, and 1,3-dichloropropene did not induce reciprocal translocations in D. melanogaster. A data audit was conducted on the Telone II&reg; 2-year carcinogenesis studies in rats and mice and the ancillary studies in rats. Except for the already known problem of survival of male vehicle control mice, no other discrepancies or problems that would compromise the validity of the findings or alter the interpretations of these studies were found. Under the conditions of these gavage studies, there was clear evidence of carcinogenicity for male F344/N rats, as indicated by Telone II&reg;-related increased incidences of squamous cell papillomas and carcinomas of the forestomach, as well as an increased incidence of neoplastic nodules of the liver. In female F344/N rats, there was some evidence of carcinogenicity because Telone II&reg; caused an increased incidence of squamous cell papillomas of the forestomach. The experiment in male B6C3F1 mice was considered to be an inadequate study of carcinogenicity because of reduced survival in the vehicle control group. However, there was some indication in the male mice of Telone II&reg;-related increases of transitional cell carcinomas of the urinary bladder, squamous cell papillomas of the forestomach, and alveolar/bronchiolar adenomas and carcinomas of the lung. There was clear evidence of carcinogenicity for female B6C3F1 mice, since Telone II&reg; caused increased incidences of transitional cell carcinomas of the urinary bladder; Telone II&reg; also increased the incidences of alveolar/bronchiolar adenomas of the lung and of squamous cell papillomas or carcinomas of the forestomach in the female mice. Telone II&reg;-related nonneoplastic lesions included basal cell or epithelial cell hyperplasia in the forestomach of male and female rats and male and female mice and epithelial hyperplasia of the urinary bladder in male and female mice. Synonyms: cis,trans-1,3-dichloropropene, D-D&reg; Soil Fumigant; Telone&reg; Soil Fumigants; Vorlex&reg; Soil Fumigants

Journal Article↗
PubMed1985

NTP Toxicology and Carcinogenesis Studies of Propylene Oxide (CAS no. 75-56-9) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

Propylene oxide is a volatile, colorless liquid used as an intermediate in the production of polyether polyols, polyurethane foams, and unsaturated polyester resins and also as a fumigant for sterilizing a variety of materials ranging from plastic medical instruments to foodstuffs. In the United States, propylene oxide is registered as a fumigant for packaged dried prunes and glacé fruits such as candied cherries and as an insecticidal and fungicidal fumigant for bulk quantities of cocoa, gums, and processed spices. The 2-year carcinogenesis studies of propylene oxide (greater than 99.9% pure) were conducted by exposing groups of 50 F344/N rats and 50 B6C3F1 mice of each sex to air containing propylene oxide at concentrations of 0 (chamber control), 200, or 400 ppm for 6 hours per day, 5 days per week, for 103 weeks. The survival of rats exposed to propylene oxide was comparable with that of the controls; terminal body weights were lower than those of the controls for high dose males (8%) and high dose females (6%). Survival of exposed male and female mice decreased relative to that of the controls (male: control, 42/50; low dose, 34/50; high dose, 29/50; female: 38/50; 29/50; 10/50), but the difference was significant only for animals in the high dose groups. High dose female mice had a mean terminal body weight 22% below that of the controls. The respiratory epithelium of the nasal turbinates was one of the primary tissues affected in male and female rats; exposure-related increases occurred in the incidences of suppurative inflammation, epithelial hyperplasia, and squamous metaplasia. Papillary adenomas, involving the respiratory epithelium and underlying submucosal glands of the nasal turbinates, were observed in three female rats and two male rats exposed to propylene oxide at 400 ppm. The incidence of adenomas in females was significant by the trend tests. The proportions of high dose female rats with C-cell adenomas and with C-cell carcinomas of the thyroid gland were increased, but only the combined incidence of these tumors was significant (2/45; 2/35; 7/37). These tumors were not considered to be related to exposure to propylene oxide because there was no other evidence for C-cells' being a target tissue and because there was no increase in C-cell hyperplasia. The combined incidences of female rats with endometrial stromal polyps and endometrial stromal sarcomas of the uterus were significantly increased in the dosed groups (3/49; 12/50; 10/47). However, the occurrence of these lesions in the dosed groups was similar to the average (306/1,502, 20%) seen in untreated controls in NTP carcinogenesis studies, and hence this increase was not regarded as being related to exposure to propylene oxide. The respiratory epithelium of the nasal turbinates was also one of the primary tissues affected in male and female mice; exposure-related increases occurred in the incidences of inflammation, and squamous metaplasia was observed in one low dose male and two high dose female mice. One squamous cell carcinoma and one papilloma occurred in the nasal cavity of different high dose male mice, and two high dose female mice had adenocarcinomas of the nasal cavity. The endothelial cells of the submucosal vascular plexus in the nasal turbinates also appeared to be a major site affected in high dose male mice. Three high dose male and three high dose female mice had a saccular dilation (classified as angiectasis) of submucosal turbinate vessels. Further, hemangiomas were seen in the nasal cavity of 5/50 high dose male mice and 3/50 high dose female mice, and hemangiosarcomas were found in the nasal cavity of 5/50 high dose male mice and 2/50 high dose female mice. The increased incidences of hemangiomas in males and females and of hemangiosarcomas in males were statistically significant. Vascular tumors were not present in the nasal turbinates of any low dose or control mice. Under the conditions of these studies, there was some evidence of carcinogenicity for F344/N rats, as indicated by increased incidences of papillary adenomasncreased incidences of papillary adenomas of the nasal turbinates in male and female rats exposed to propylene oxide at 400 ppm. For male and female B6C3F1 mice, there was clear evidence of carcinogenicity, as indicated by increased incidences of hemangiomas or hemangiosarcomas of the nasal turbinates at 400 ppm. In the respiratory epithelium of the nasal turbinates, propylene oxide also caused suppurative inflammation, hyperplasia, and squamous metaplasia in rats and inflammation in mice.

Journal Article↗
PubMed1985

NTP Toxicology and Carcinogenesis Studies of Chlorobenzene (CAS No. 108-90-7) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Chlorobenzene is a colorless, volatile liquid under standard environmental conditions (vapor pressure=11.8 mm Hg at 25 degrees C, 760 mm Hg). It is used primarily as a solvent (e.g. resins, dyes, pesticides, and perfumes), a degreasing agent, and a chemical intermediate, particularly in the synthesis of nitrobenzenes. Although still considerable, estimates of the yearly production volume of chlorobenzene in the United States indicate declining use in recent years, due to the reduced demand for organochlorine pesticides utilizing chlorobenzene as an intermediate. Toxicology and carcinogenesis studies of chlorobenzene (<99% pure) were conducted by administering the test chemical in corn oil by gavage to groups of 50 male and 50 female F344/N rats and 50 female B6C3F1 mice at doses of 60 or 120 mg/kg. Groups of 50 male B6C3F1 mice received 30 or 60 mg/kg. Chlorobenzene was administered five times per week for 103 weeks. Groups of 50 rats and 50 mice of each sex received corn oil by gavage on the same schedule and served as vehicle controls, and additional groups of 50 rats and 50 mice of each sex served as untreated controls. The chlorobenzene doses were chosen on the basis of 90-day studies, in which doses 2-fold or greater in excess of the doses used in the 2-year study caused death, hepatocellular necrosis, renal tubular injury, thymic necrosis, or lymphoid or myeloid depletion of bone marrow, spleen or thymus. Mean body weights of dosed rats and mice were essentially the same or greater than those of the controls during the 2-year studies. Survivals of low dose male rats, dosed female rats, dosed male mice, and dosed female mice were not adversely affected by administration of chlorobenzene. Survival of high dose male rats in the 2-year study was significantly (P=0.033) lower than that of the vehicle controls. No chlorobenzene-induced toxic lesions responsible for this reduction in survival were observed. Based on the prechronic results and on the above data, the doses used in the 2-year study were considered to be adequate for carcinogenicity testing. Male rats dosed with chlorobenzene exhibited a significant (P<0.05) increase in the incidence of animals with neoplastic nodules of the liver (overall incidences: untreated control, 4/50 (8%); vehicle control, 2/50 (4%); low dose, 4/49 (8%); high dose, 8/49 (16)). Increased incidences of hepatocellular carcinomas in male rats or of neoplastic nodules or hepatocellular carcinomas in female rats were not observed. No increased tumor incidences were observed in female rats or in male or female mice. Under the conditions of these studies, chlorobenzene administration increased the occurrence of neoplastic nodules of the liver in high dose (120 mg/kg/day) male F344/N rats, providing some but not clear evidence of carcinogenicity of chlorobenzene in male rats. Carcinogenic effects of chlorobenzene were not observed in female F344/N rats or in male or female B6C3F1 mice. Levels of Evidence of Carcinogenicity: Male Rats: Equivocal Female Rats: Negative Male Mice: Negative Female Mice: Negative Synonyms: monochlorobenzene; chlorobenzol; phenyl chloride; benzene monochloride

Journal Article↗
PubMed1985

NTP Toxicology and Carcinogenesis Studies of 1,2-Dichlorobenzene (o-Dichlorobenzene) (CAS No. 95-50-1) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

The major use of 1,2-dichlorobenzene is as an intermediate in the synthesis of several organic compounds (e.g. 3,4-dichloroaniline) and in the syntheses of the herbicides propanil, diuron, and neburon. It is used as an industrial solvent for toluene diisocyanate, an additive to degreasing agents, a heat exchange medium, a deodorant for garbage and sewage, an ingredient in paint removers, an engine cleaner and de-inking solvent, and a solvent and intermediate in dye manufacture). 1,2-Dichlorobenzene is also used as an insecticide and a fumigant to control peach tree borers, bark beetles, grubs, and termites and to kill mites and other insects in poultry houses and animal sleeping quarters. Because of its properties as both an insecticide and a solvent, 1,2-dichlorobenzene has been used in low-pressure aerosol formulations of insecticides. Approximately 49 million pounds of 1,2-dichlorobenzene were produced in the United States in 1980. First reported commercial production began in 1921. In 13-week studies using F344/N rats and B6C3F1 mice, 500 mg/kg of 1,2-dichlorobenzene (<99% pure) decreased survival in male and female mice and female rats when administered in corn oil by gavage five times per week. At this dose, 1,2-dichlorobenzene produced centrolobular necrosis of the liver, hepatocellular degeneration, and depletion of lymphocytes in the thymus and spleen of both sexes of rats and mice. At a dose of 250 mg/kg, necrosis of individual hepatocytes was observed in both sexes of rats and in male mice. Minimal hepatocellular necrosis was observed in a few rats at a dose of 125 mg/kg, but no hepatic alterations were observed in mice at this dose. Renal tubular degeneration was observed in male rats at 500 mg/kg, and multifocal mineralization of the myocardial fibers of the heart and skeletal muscle were seen in mice. The only hematologic changes considered notable were slight decreases in hemoglobin and hematocrit in the 500 mg/kg male and female rats and in red blood cell counts in the 500 mg/kg male rats; no other marked hematological changes were observed in either species. Two-year toxicology and carcinogenesis studies of 1,2-dichlorobenzene were conducted by administering the test chemical in corn oil gavage five times per week for 103 weeks to groups of 50 male and 50 female F344/N rats and B6C3F1 mice at doses of 60 and 120 mg/kg. Groups of 50 rats and 50 mice of each sex received corn oil by gavage on the same schedule and served as vehicle controls. Survivals of female rats, male mice, and female mice were comparable to those of the corresponding vehicle controls in the 2-year study, but survival of high dose male rats was (P<0.001) shorter than that of the vehicle controls. In this group there were three accidental deaths and five deaths probably due to the gavage process; in addition aspiration of 1,2-dichlorobenzene in corn oil into the lungs may have been a contributing factor to the deaths of 12 high dose male rats. The 120 mg/kg dose level of 1,2-dichlorobenzene did not affect body weight in rats or mice of either sex or survival of mice or female rats. An increase in tubular regeneration in the kidney of high dose male mice was observed in the 2-year study (control, 8/48, 17%; low dose, 12/50, 24%; high dose, 17/49, 35%). No other compound-related nonneoplastic histological lesions were noted in the 2-year study. The incidence of pheochromocytoma of the adrenal gland in low dose male rats was elevated (P<0.05, life table test) relative to controls (9/50, 16/50, 6/49). However, the incidence in the high dose group was lower than that of the controls and the dose-response trend was not statistically significant. Therefore, the increase in pheochromocytoma in the low dose male rats is not regarded as related to administration of 1,2-dichlorobenzene. A dose-related increase (P<0.05) in malignant histiocytic lymphoma was observed in male mice (control, 0/50, 0%; low dose, 1/50, 2%; high dose, 4/50, 8%) and in female mice (0/49, 0%; 0/50, 0%; 3/49, 6%); however, comparisons of the numbers of animals with all typnt;; 3/49, 6&percnt;); however, comparisons of the numbers of animals with all types of lymphomas is considered to be a more appropriate comparison. 1,2-Dichlorobenzene did not increase the incidence of all types of lymphomas (combined) in male mice (8/50, 16&percnt;; 2/50, 4&percnt;; 4/50, 8&percnt;) or female mice (11/49, 22&percnt;; 11/50, 22&percnt;; 13/49, 27&percnt;). Therefore, the increase in histiocytic lymphomas was discounted. Under the conditions of these two-year gavage studies, there was no evidence of carcinogenicity of 1,2-dichlorobenzene for male or female F344/N rats or B6C3F1 mice receiving 60 or 120 mg/kg per day. Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative Male Mice: Negative Female Mice: Negative Synonym: o-dichlorobenzene

Journal Article↗
PubMed1985

NTP Toxicology and Carcinogenesis Studies of Diallylphthalate (CAS No. 131-17-9) in F344/N Rats (Gavage Studies).

Diallylphthalate is widely used as a crosslinking agent for unsaturated polyesters. Diallylphthalate or diallylphthalate polyester blends are used primarily as plasticizers and carriers for adding catalysts and pigments to polyesters and in molding, electrical parts, laminating compounds, and impregnation of metal castings. Rubber compounds, epoxy formulations, and polyurethane foams may also contain diallylphthalate. Precise figures are not currently available, although annual production of diallylphthalate in the United States is known to exceed 5,000 pounds, and an estimated 57,000 pounds were imported into the United States in 1982. Toxicology and carcinogenesis studies of diallylphthalate (approximately 99% pure) were conducted by administering the test chemical in corn oil by gavage to groups of 50 male and 50 female F344/N rats at doses of 0 (vehicle control), 50, or 100 mg/kg 5 days per week for 103 weeks. The diallylphthalate doses used in the 2-year studies were chosen on the basis of 13-week studies, wherein doses of 200 or 400 mg/kg caused death, reductions in body weight gains, or periportal hepatocellular necrosis and fibrosis in both sexes. Mean body weights and survival of male and female rats administered diallylphthalate were essentially the same as those of the vehicle controls throughout the 2-year studies, although hepatotoxicity was produced in both sexes by the 100 mg/kg dose. Based on the results of the prechronic studies and the effects on the liver in the 2-year studies, the doses used in the 2-year studies were considered to be adequate for carcinogenicity testing. Male and female rats receiving the 100 mg/kg dose of diallylphthalate in the 2-year studies developed chronic liver diseases characterized by periportal fibrosis, periportal accumulation of pigment, and severe bile duct hyperplasia. Pigment accumulation also occurred at the 50 mg/kg dose in both sexes. Diallylphthalate administration increased the occurrence of mononuclear cell leukemia in female rats (P<0.05 by trend tests), and the increase in the 100 mg/kg dose female rats was greater (P</=0.05) than in the vehicle controls by pairwise comparisons (vehicle control, 15/50, 30%; low dose, 15/43, 35%; high dose, 25/49, 51%). An increased occurrence of mononuclear cell leukemia was not observed in male rats receiving diallylphthalate. A previous NTP carcinogenesis study (NTP TR 242) reported an increased incidence of lymphomas in male B6C3F1 mice receiving diallylphthalate by gavage for 2 years at doses of 0, 150, or 300 mg/kg. This increase was considered to be equivocally related to diallylphthalate administration. The incidences of hyperplasia and inflammatory lesions of the forestomach were increased in a dose-related fashion in both sexes of mice in that study, and uncommon forestomach papillomas were observed in 0%, 2%, and 4% of both sexes of mice. Because of the numerical increase in forestomach papillomas, the concomitant presence of forestomach hyperplasia, and the rarity of forestomach papillomas in vehicle control (corn oil gavage) B6C3F1 mice, the development of these proliferative lesions of the forestomach in mice may have been related to diallylphthalate administration. In the current study in rats, a squamous cell carcinoma was found in one high dose male rat. Diallylphthalate was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without activation by a 9,000 x g supernatant fraction from the livers of Aroclor 1254-treated male Sprague-Dawley rats or Syrian hamsters. Diallylphthalate did not induce sex-linked recessive lethal mutations in Drosophila melanogaster. An audit of the experimental data was conducted for these carcinogenicity studies on diallylphthalate. No data discrepancies were found that influenced the final interpretations. Under the conditions of this study, the administration of diallylphthalate by gavage in corn oil to male and female F344/N rats for 2 years caused chronic liver disease characterized by periportal fibrosis and pigment accumulation and an increasetal fibrosis and pigment accumulation and an increased severity of bile duct hyperplasia. The incidence of mononuclear cell leukemia was significantly increased in female rats receiving 100 mg/kg. Because of the variability in the incidence of this neoplasm in aged Fisher 344 rats and the difficulty in definitively diagnosing this lesion in Fisher 344 rats, this increase was considered to be equivocal evidence of carcinogenicity of diallylphthalate in female rats. There was no evidence of carcinogenicity in male rats. Synonym: DAP

Journal Article↗
PubMed1985

NTP Toxicology and Carcinogenesis Studies of Chlorodibromomethane (CAS No. 124-48-1) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Toxicology and carcinogenesis studies of chlorodibromomethane (greater than 98% pure), a trihalomethane formed after chlorination of water supplies, were conducted by administering this test chemical in corn oil gavage five times per week for 104 weeks to groups of 50 male and 50 female F344/N rats at 0,40, or 80 mg/kg per day and to groups of 50 male and 50 female B6C3F1 mice for 105 weeks at doses of 0, 50, or 100 mg/kg per day. Survival of dosed male and female rats and female mice was comparable to that of the corresponding vehicle control groups. An overdose of chemical was given to low dose male and female mice at week 58; this overdose killed 35 male mice, whereas the female mice were apparently not affected. Because this mortality significantly reduced the number of survivors, the low dose male mouse group was considered to be inadequate for analysis of neoplasms. High dose male mice had lower survival than the vehicle controls (44/50 vs 29/50; P<0.001). At week 82, nine high dose male mice had died; the cause remains unknown. High dose male rats and dosed male and female mice had lower body weights compared with those of the vehicle controls. Compound-related nonneoplastic lesions were found in the liver and kidney in male and female rats and in male mice in the 13-week studies at the highest dose (250 mg/kg). In the 2-year studies, compound-related toxicity was seen primarily in the livers of male and female rats (fatty metamorphosis and ground-glass cytoplasmic changes) and in the male mice (hepatocytomegaly, necrosis, fatty metamorphosis) and female mice (calcification and fatty metamorphosis). Toxicity was also seen in the kidneys (nephrosis) of male mice and female rats. Administration of chlorodibromomethane significantly increased the incidence of hepatocellular adenomas (vehicle control, 2/50; low dose, 4/49; high dose, 11/50) and the combined incidences of hepatocellular adenomas or carcinomas (6/50; 10/49; 19/50) in high dose female mice. The incidence of hepatocellular carcinomas (vehicle control, 10/50; high dose, 19/50) was significantly increased in high dose male mice, although the combined incidence of hepatocellular adenomas or carcinomas (vehicle control, 23/50; high dose, 27/50) was marginally significant by the life table test but not by the incidental tumor test. Negative trends in several common rodent tumors were found in dosed animals in the 2-year studies. These neoplasms included fibroadenomas of the mammary gland in female rats, endometrial stromal polyps of the uterus in female rats, and malignant lymphomas in male mice. Chlorodibromomethane was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 in the presence or absence of Aroclor-induced male Sprague-Dawley rat or male Syrian hamster liver S9. An audit of the experimental data was conducted for the 2-year toxicology and carcinogenesis studies of chlorodibromomethane. No data discrepancies were found that influenced the final interpretations. Under the conditions of these gavage studies, there was no evidence of carcinogenicity in male or female F344/N rats receiving chlorodibromomethane at doses of 40 or 80 mg/kg five times per week for 104 weeks. Fatty metamorphosis and ground-glass cytoplasmic changes of the liver in male and female F344/N rats were related to administration of chlorodibromomethane. There was equivocal evidence of carcinogenicity for male B6C3F1 mice; chlorodibromomethane caused an increased incidence of hepatocellular carcinomas, whereas the combined incidence of hepatocellular adenomas or carcinomas was only marginally increased. Some evidence of carcinogenicity was observed for female B6C3F1 mice, since chlorodibromomethane caused an increased incidence of hepatocellular adenomas and an increased combined incidence of hepatocellular adenomas or carcinomas. Synonym: Dibromochloromethane

Journal Article↗
PubMed1985

NTP Toxicology and Carcinogenesis Studies of 8-Hydroxyquinoline (CAS No. 148-24-3) in F344/N Rats and B6C3F1 Mice (Feed Studies).

Carcinogenesis studies of 8-hydroxyquinoline (99% pure), a metal chelator and antimicrobial agent, were conducted by administering the test chemical in feed to groups of 50 male and 50 female F344/N rats and B6C3F1 mice at concentrations of 0, 1,500, or 3,000 ppm for 103 weeks. These concentrations were selected because the chemical at higher concentrations resulted in reduced feed consumption, decreases in mean body weights, and deaths in the 15-day and 13-week studies. The average daily doses were estimated to be 73 and 143 mg/kg for male rats, 89 and 166 mg/kg for female rats, 217 and 396 mg/kg for male mice, and 349 and 619 mg/kg for female mice. Survival of dosed male and female rats and mice in the 2-year studies was comparable to that of the corresponding controls. The high dose rats and mice of each sex exhibited slight decreases in mean body weights and decreased feed consumption. Compound-related gross or microscopic pathologic effects were not observed in either species in the 15-day or 13-week studies. In the 2-year studies, C-cell adenomas/carcinomas of the thyroid gland showed a positive trend (P=0.03) for male rats (control, 1/50; low dose, 1/49; high dose, 6/47). The incidence of C-cell neoplasms in the high dose was not significantly increased compared with the controls, and the occurrence of C-cell hyperplasia was not elevated (4/50; 3/49; 1/47). The incidence of alveolar/bronchiolar adenomas or carcinomas (combined) in male rats with a positive trend, and the incidence in the high dose group was greater than that in the controls (0/50; 3/50; 4/50). This marginal effect was not supported by an increase in epithelial hyperplasia (5/50; 5/50; 3/50). These marginal increases in male rats were not regarded as being related to the administration of 8-hydroxyquinoline. In in vitro tests, 8-hydroxyquinoline did not induce either unscheduled DNA synthesis in rat hepatocytes or transformation of BALB/c-3T3 cells. An audit of the experimental data for these carcinogenesis studies on 8-hydroxyquinoline was conducted. No data discrepancies were found that significantly influenced the final interpretations. Under the conditions of these studies, there was no evidence of carcinogenicity for male and female F344/N rats or for male and female B6C3F1 mice given 8-hydroxyquinoline in feed at concentrations of 1,500 or 3,000 ppm for 103 weeks. Synonyms: 8-quinolinol; oxine; hydroxybenzopyridine

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PubMed1985

NTP Toxicology and Carcinogenesis Studies of 2-Chloroethanol (Ethylene Chlorohydrin) (CAS No. 107-07-3) in F344/N Rats and Swiss CD-1 Mice (Dermal Studies).

Toxicology and carcinogenesis studies of 2-chloroethanol (99% pure), an industrial chemical and an intermediate in the synthesis of ethylene oxide, were conducted by dermal application of 2-chloroethanol dissolved in 70% ethanol:30% water (v/v) solutions to groups of 50 F344/N rats of each sex at doses of 0, 50, or 100 mg/kg for 103 weeks or to groups of 50 Swiss CD-1 mice of each sex at doses of 0, 7.5, or 15 mg per animal for 104 weeks (0, 253, or 630 mg/kg at week 1; 0, 180, 411 mg/kg at week 100). The control groups received skin applications of the vehicle; the mouse studies also included untreated control groups of 50 male and 50 females. 2-Chloroethanol solutions were applied to the clipped interscapular area of the animals once daily, 5 days per week for the test period. Rats received a volume of 0.18-0.22 ml of solution; mice received 0.10 ml of solution. In the 13-week studies, mortality was observed in male and female rats receiving 20 mg per day and higher. In the 104-week studies, the survival of high dose male mice was lower (P<0.05) than that of the vehicle controls (vehicle control, 26/50; 7.5 mg, 16/50; 15 mg, 12/50). Body weights of dosed mice were unaffected by 2-chloroethanol. The survival and body weight gain data suggest that the male and female rats and female mice could have tolerated a higher dose of 2-chloroethanol. Male mice probably could not have tolerated a higher dose than was applied to the skin. Seven high dose male mice died within 3 days of the start of dosing; all of these had inflammation at the site of dermal application. Five also had ulceration at the site of dermal application, and five had lung congestion, inflammation, or hemorrhage. Marginal increases were found in the incidence of lymphomas or leukemias (combined) as well as in the incidence of alveolar/bronchiolar adenomas or carcinomas (combined) in low dose male mice. Since there was no dose-related trend for these tumor incidences and because the increases were observed in only one sex, the increases were not considered to be related to the dermal application of 2-chloroethanol. 2-Chloroethanol was mutagenic in Salmonella typhimurium strains TA100 and TA1535 (but not TA1537 or TA98) in either the presence or the absence of Aroclor 1254-induced male Sprague-Dawley rat or Syrian hamster liver S9. 2-Chloroethanol did not induce sex-linked recessive lethal mutations in Drosophila melanogaster. An audit of the experimental data was conducted for these 2-year studies. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year dermal studies, there was no evidence of carcinogenicity of 2-chloroethanol for male and female F344/N rats given 50 or 100 mg/kg per day or for male and female Swiss CD-1 mice given 7.5 or 15 mg per animal per day. Synonyms: ethylene chlorohydrin; chloroethanol; glycol chlorohydrin; b-chloroethanol

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PubMed1985

NTP Toxicology and Carcinogenesis Studies of Chrysotile Asbestos (CAS No. 12001-29-5) in F344/N Rats (Feed Studies).

Lifetime toxicology and carcinogenesis studies of short-range (SR) and intermediate-range (IR) fiber length chrysotile asbestos were conducted in groups of 88-250 male and female F344/N rats. Both forms of asbestos were administered at a concentration of 1% in pelleted diet for the lifetime of the rats, starting with the dams of the test animals. Subgroups of 100 male and female IR chrysotile-exposed rats also received 0.47 mg/g IR chrysotile asbestos in water by gavage during lactation (preweaning [PW]). At 9 weeks of age, additional subgroups (125-175) of control and IR chrysotile-exposed rats received 7.5 mg/kg (male) or 15 mg/kg (female) 1,2-dimethylhydrazine dihydrochloride (DMH) by gavage every other week for a total of five doses. When the survival of either the control or test group reached 10%, both groups were killed. Neither type of fiber affected fertility or litter size. The offspring from mothers exposed to SR chrysotile were similar in body weight to the controls at birth but were slightly smaller (13%) at weaning and remained so throughout their lifetimes. Feed consumption and survival were comparable among the SR and IR chrysotile asbestos groups and controls. The DMH-exposed groups showed decreased survival due primarily to the development of lethal neoplasms. The administration of SR chrysotile for the lifetime of exposed male and female rats did not cause any overt toxicity. In addition, no neoplastic or nonneoplastic disease was associated with SR chrysotile exposure. Male and female rats exposed to IR chrysotile asbestos did not show any adverse clinical signs. Benign epithelial neoplasms (adenomatous polyps) were observed in the large intestine of IR chrysotile asbestos male rats (9/250, 3.6%). Although not statistically significant (P=0.08) compared with concurrent controls (0/85), the incidence of these neoplasms was highly significant (P=0.003) when compared with the incidence of epithelial neoplasms (benign and malignant combined) of the large intestine in the pooled male control groups of all the NTP oral asbestos lifetime studies (3/524, 0.6%). The biologic importance of this finding was supported by the observation of lesions of similar morphology in the small intestine or glandular stomach of four additional IR chrysotile male rats and by a low incidence (2/100, 2.0%) of adenomatous polyps in the large intestine of male rats in the IR/PW group. A significant (P<0.05) increase in keratoacanthomas of the skin was observed in male IR (19/250, 7.6%) and IR/PW (8/100, 8.0%) chrysotile-exposed rats compared with the concurrent controls (1/88, 1.1%). The biologic importance of this observation was discounted because the incidence in these groups did not greatly exceed the rate observed in the combined male control groups from all the other NTP oral asbestos studies (19/441, 4.3%). An apparent increase in the incidence of clitoral gland neoplasms in female IR (18/250, 7.2%) and IR/PW (4/100, 4.0%) chrysotile-exposed rats compared with that in the concurrent controls (1/88, 1.1%) was also discounted because of a lack of statistical significance when compared with the pooled female control groups from the other NTP oral asbestos studies (21/441, 4.8%). Rats exposed to DMH and DMH plus IR chrysotile asbestos exhibited neoplasia in those organs known to be targets for DMH (gastrointestinal tract, Zymbal gland, liver, and kidney). There was a significant difference (P<0.05) in the incidence of DMH-induced mixed-cell tumors of the kidney between the DMH alone (13/125, 10%) and DMH plus IR chrysotile asbestos (34/175, 19%) female groups. An increased incidence of thyroid follicular cell tumors was observed in DMH plus IR chrysotile male rats (28/175, 16.0%) compared with the DMH alone group (9/124, 7.3%). The biologic importance of both observations is questionable, since neither organ represents a primary target organ for asbestos and no difference between DMH and DMH plus IR chrysotile was observed for the primary target organs (intestine and mesothelium). An audit of the experimental data was conducteIR chrysotile was observed for the primary target organs (intestine and mesothelium). An audit of the experimental data was conducted for these lifetime carcinogenesis studies of chrysotile asbestos. No data discrepancies were found that influenced the final interpretations. Under the conditions of these lifetime studies, short-range and intermediate-range chrysotile asbestos did not induce overt toxicity and did not affect survival when ingested at a level of 1&percnt; in the diet by male and female F344/N rats. There was no evidence of carcinogenicity in male or female rats exposed to SR chrysotile asbestos or in female rats exposed to IR chrysotile asbestos. There was some evidence of carcinogenicity in male rats exposed to IR chrysotile asbestos as indicated by an increased incidence of adenomatous polyps in the large intestine. The cocarcinogenesis studies of 1,2-dimethylhydrazine dihydrochloride and IR chrysotile asbestos were considered inconclusive for determining whether IR chrysotile asbestos had either a tumor-enhancing or protective effect, although an increased incidence of neoplasms was observed in the kidneys of female rats exposed to DMH plus IR chrysotile as compared with those exposed to DMH alone.

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PubMed1985

NTP Toxicology and Carcinogenesis Studies of HC Blue No. 2 [2,2'-((4-((2-Hydroxyethyl)amino)-3-nitrophenyl)imino)bis(ethanol)] (CAS No. 33229-34-4) in F344/N Rats and B6C3F 1 Mice (Feed Studies).

Toxicology and carcinogenesis studies of HC Blue No. 2 (approximately 98% pure), a semipermanent hair dye, were conducted by administering the test chemical in feed for 103 weeks to groups of 50 F344/N rats of each sex and for 104 weeks to groups of 50 B6C3F 1 mice of each sex. The dietary concentrations used were 0, 5,000, or 10,000 ppm for male rats and male mice and 0, 10,000, or 20,000 ppm for female rats and female mice. These concentrations were selected on the basis of results from single-administration gavage and 14-day and 13-week feed studies. For the 2-year studies, the average daily doses were approximately 195 and 390 mg/kg in male rats, 465 and 1,000 mg/kg in female rats, 1,320 and 2,240 mg/kg in male mice, and 2,330 and 5,600 mg/kg in female mice. The survival of high dose male rats and male mice was better than that for controls, and the survival of dosed female rats was comparable to that of the controls. The survival of high dose female mice was reduced (P<0.05) relative to that of controls (control, 35/50; low dose, 27/50; high dose 19/50); this reduced survival was attributed to a reproductive tract infection. Final mean body weights relative to those of controls were depressed less than 10% in dosed male rats, whereas depressions of 13% and 22% were observed in the low dose and high dose groups of female rats. Final mean body weights for dosed male mice were within 5% of control values, but final mean body weights for dosed females were 15% (low dose) and 22% (high dose) lower than that of controls. A dose-related increase in the incidence of hyperostosis of the skull was detected in rats (male, 5/50, 8/50, 25/49; female, 2/50, 19/50, 49/50) and in 1/49 high dose male and 4/50 high dose female mice. Mixed mesenchymal neoplasms of the kidney were detected in 2/50 high dose female rats; none was observed in any other group of female or male rats. This tumor is considered uncommon and has not been found in 1,863 historical control female F344/N rats. A negative trend in fibroadenomas of the mammary gland was seen in female rats (20/50, 10/50, 4/50). A marginal (P=0.05) positive trend occurred in the incidence of lymphomas in male mice (1/50; 5/48; 8/49); the incidences in the dosed groups were not significantly greater than that in the controls when survival differences were taken into account. HC Blue No. 2 was mutagenic for strains TA97 and TA98 but not for strains TA100 or TA1535 of Salmonella typhimurium in the presence or absence of Aroclor 1254-induced male Sprague-Dawley rat or Syrian hamster liver S9. HC Blue No. 2 was mutagenic in the mouse lymphoma L5178Y/TK+/- assay in the presence of Aroclor 1254-induced male F344/N rat liver S9. An audit of the experimental data was conducted for these carcinogenic studies on HC Blue No. 2. No data discrepancies were found that influenced the final interpretations. Under the conditions of these studies, there was no evidence of carcinogenicity in male and female F344/N rats or in male and female B6C3F 1 mice receiving HC Blue No. 2 in the diet at concentrations of 0.5% and 1.0% for males and 1.0% and 2.0% for females for 2 years. HC Blue No. 2 administration caused a dose-related increase in the incidence of hyperostosis of the skull in male and female rats. Synonym: 2,2'-((4-((-hydroxyethyl)amino)-3-nitrophenyl)imino)bis(ethanol)

Journal Article↗
PubMed1985

NTP Toxicology and Carcinogenesis Studies of Dimethyl Hydrogen Phosphite (CAS No. 868-85-9) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Dimethyl hydrogen phosphite (DMHP) is used as an intermediate in the production of insecticides and herbicides, as an additive to lubricants, and as a stabilizer in oil and plaster and was considered for use as a chemical to simulate the physical (but not the biologic) properties of anticholinesterase agents. Results of 13-week gavage studies in F344/N rats (0-400 mg DMHP/kg body weight) and in B6C3F1 mice (0-1,500 mg DMHP/kg body weight) were used to identify short-term toxicity and to establish doses for the 2-year toxicology and carcinogenesis studies. In these studies, dimethyl hydrogen phosphite (greater than 97% pure) was administered for 103 weeks in corn oil by gavage to groups of 50 male F344/N rats and to groups of 50 male and female B6C3F1 mice at doses of 0, 100, or 200 mg/kg and to groups of 50 female F344/N rats at doses of 0, 50, or 100 mg/kg. In the 2-year studies, survival of high dose male rats and high dose male mice was lower (P<0.05) than that of the vehicle controls (male rats: vehicle control, 39/50; low dose, 29/50; high dose, 23/50; male mice: 42/50; 34/50; 32/50). At the end of the studies, mean body weights were lower than those of the corresponding vehicle controls for high dose male rats (-15%), for high dose female rats (-5%), and for high dose male mice (-5%). Dimethyl hydrogen phosphite caused dose-related increases in nonneoplastic and neoplastic lesions of the lung in male and female rats. In high dose male rats, there were increased incidences of lung neoplasms, including squamous cell carcinomas (0/50; 0/50; 5/50), alveolar/bronchiolar adenomas (0/50; 0/50; 5/50), and alveolar/bronchiolar carcinomas (0/50; 1/50; 20/50). In high dose female rats, there was a marginal increase in the incidence of alveolar/bronchiolar carcinomas of the lung (0/50; 1/49; 3/50). Hyperplasia of the lung and chronic interstitial pneumonia were increased in dosed male rats and in high dose female rats. Dimethyl hydrogen phosphite caused increases in forestomach lesions in male and female rats. In male rats, there was an increased incidence of forestomach neoplasms, including squamous cell papillomas (0/50; 1/50; 3/50) and squamous cell carcinomas (0/50; 0/50; 3/50). High dose male rats had increased incidences of hyperkeratosis and hyperplasia of the forestomach. In high dose female rats, the incidence of forestomach hyperplasia was increased. Neoplastic lesions of the forestomach (a squamous cell papilloma and a squamous cell carcinoma) were found in two high dose female rats. Mineralization of the cerebellum was seen in high dose male rats (12/49) and in no other group. Focal calcification of the testis occurred at increased incidence in dosed male mice in the 2-year studies (2/50; 9/47; 24/50). Compound-related testicular atrophy was seen in male mice in the 13-week study. Dimethyl hydrogen phosphite did not induce any neoplasms in male or female mice. Dimethyl hydrogen phosphite was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 in the presence or absence of Aroclor 1254-induced male Sprague-Dawley rat or Syrian hamster liver S9. This chemical did not induce sex-linked recessive lethal mutations in Drosophila melanogaster. An audit of the experimental data was conducted for these carcinogenic studies on dimethyl hydrogen phosphite. No data discrepancies were found that influenced the final interpretations. Under the conditions of these gavage studies, there was clear evidence of carcinogenicity in male rats receiving dimethyl hydrogen phosphite, as shown by increased incidences of alveolar/bronchiolar adenomas, alveolar/bronchiolar carcinomas, and squamous cell carcinomas of the lung and of neoplasms of the forestomach. There was equivocal evidence of carcinogenicity in female F344/N rats receiving dimethyl hydrogen phosphite, as shown by marginally increased incidences of alveolar/bronchiolar carcinomas of the lung and of neoplasms of the stomach. There was no evidence of carcinogenicity in male or female B6C3F1 mice receiving dimethyl hydrogen phosphite at doses of 100 ogen phosphite at doses of 100 or 200 mg/kg for 103 weeks. Synonyms: phosphonic acid, dimethyl ester (9CI); dimethyl phosphite; dimethyl phosphorus acid; methyl phosphonate; dimethyl phosphonate; dimethoxyphosphine oxide; TL 585; DMHP; phosphorous acid, dimethyl ester; dimethylphosphite; dimethyl phosphonate; dimethylphosphorous acid; bis(hydroxymethyl) phosphine oxide

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