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PubMed2000

The FAA's postmortem forensic toxicology self-evaluated proficiency test program: the first seven years.

Existing proficiency-testing (PT) programs do not address the complexity of postmortem forensic toxicology. These programs do not include decomposed samples and solid tissues. Therefore, the Federal Aviation Administration in July 1991 started such a needed PT program. This program is used to: (i) professionally develop and maintain technical currency on a voluntary, interlaboratory, and self-evaluation basis, and (ii) quantifiably assess methods in the absence and presence of interfering substances. There are currently about 30 laboratories in the program. Functioning under various governmental/non-governmental agencies and academic institutions, these laboratories represent a broad cross-section of the country. PT samples are distributed quarterly, and result summaries are sent to the participants, while maintaining their anonymity. Since the inception of the program, 28 PT samples encompassing whole blood, plasma, urine, kidney, or liver, with (or without) drugs, metabolites, and common chemicals (nicotine, caffeine, beta-phenylethylamine, etc.) have been analyzed by the participants. Analytical findings were generally consistent with the anticipated values, but they were dependent on the nature and conditions of the specimens and types of the added analytes. Some incidences of false positives of concern were noted, as well. This PT program is one of the few programs recommended by the American Board of Forensic Toxicology in which laboratories may participate for their accreditation by the Board. It is anticipated that this PT program will continue to play a critical part in supporting the quality assurance/quality control (QA/QC) component of forensic toxicology, thereby enhancing operational performance.

Accidents, Aviation↗

PubMedDate not supplied

[Use of the CD-ROM "Tox-Didact" for teaching of toxicology and pharmacology].

Tox-Didact is a multimedia teaching software package for initial training, continuing training and self-learning of toxicology and pharmacology. This software covers a large part of toxicology in its acute and chronic pathology using several approaches: drugs (salicylics, paracetamol, lithium ...); toxins (lead, methanol, carbon monoxide ...); drug addiction and doping (cocaine, heroin, LSD, amphetamines ...); systemic targets (kidneys, skin, liver ...). Tox-Didact is currently composed of 39 modules in validation, each tackling the diagnosis, biological surveillance, treatment, prevention and documentation of a real clinical case. Each module is organized around four types of questions, requiring a choice either (drug, symptom, formula ...) or an open response. Each validated answer is analysed by software which then comments on or corrects it. The essential points which characterize this software are: its multidisciplinarity (toxicology, pharmacology, semiology ...), its reliability (validated by experts), its simplicity of use. It is modular and offers an interactive teaching approach. The objective is to create a portable multimedia tool operational with all computer systems (IBM PC, Macintosh). This program is sustained by the Région des Pays de la Loire and by the Multimedia Resource Office of the French Ministry of National Education.

CD-ROM↗

PubMed2000

The snake as the symbol of medicine, toxicology and toxinology.

We investigated the meaning and the roots of the snake's usage as a symbol of medicine, the medical profession, toxicology and toxinology by examining mythological, archeological data and a variety of texts from the ancient Greek world. The snake figure was associated with Asclepios, the ancient Greek God of medicine, and possessed benevolent properties. It was believed to be able to cure a patient or a wounded person just by touch. The snake is also connected with pharmacology and antisepsis, as snakes possess an antivenom against their own poison. The snake is related to sciences associated with poison and death, such as toxicology and toxinology, and it also implies a metaphysical idea. It is connected with the underworld, not only because it crawls on the ground, but because it can bring death, connecting the upper with the underground world. The ability of the snake to shed its skin has been associated with the circle of life, and the renaissance spirit also, ever since early Hellenic antiquity. Consequently, as a symbol of the modern medical profession, toxicology and toxinology, the snake twisted around a stick or the snake beside a pharmapeutic cup, which also implies the use of medicines or even poison, has its roots in the ancient Mediterranean area as proven by the archeological data combined with literary references. Its benevolent as well as its poisonous properties could be paralleled by the similar properties of medicines.

Animals↗

PubMed2000

[Effect of drinking water on animal health: toxicologic health risks].

To avoid health risks in farm animals it is necessary to limit the intake of unwanted chemical compounds via air, feed or drinking water. The basis for this procedure are experimental results of Veterinary Toxicology, after which acceptable daily intakes can be estimated. A health risk is not present, if those limits are not exceeded. Risks may not only occur as an impairment of health itself but as well as a reduction of yield of food producing animals (body growth, production of meat and fat, fertility, milk and egg production). In addition the cumulation of unwanted compounds in tissues, which are used for the production of food of animal origin, is of great importance for the limitation of daily intakes of those environmental pollutants. Following the results of toxicological experiments in the target animals "Toxicological Drinking Water Standards for Animals" can be established.

Animal Husbandry↗

PubMed2000

[Medico-legal certification of fatal cases after drug: abuse in the light of modern toxicological analysis].

Introduction of modern instrumental methods for toxicological analysis make possible a detection and identification of xenobiotics in different kind of multicomponents biological samples (plant sources of narcotics, body fluids and tissues of abusers) on a low concentration level. In this way a range of possibilities for the interpretation of toxicological results was enlarged. General medicolegal trends are strictly connected with modern analytics and they can be discussed on the basis of drug--users and fatal cases of intoxications with narcotics. Toxicological findings of these cases were worked out by means of modern analytical method--liquid chromatography with mass detection (LC/MS).

Adolescent↗

PubMed2002

Collection analysis techniques used to evaluate a graduate-level toxicology collection.

Collections librarians from academic libraries are often asked, on short notice, to evaluate whether their collections are able to support changes in their institutions' curricula, such as new programs or courses or revisions to existing programs or courses. With insufficient time to perform an exhaustive critique of the collection and a need to prepare a report for faculty external to the library, a selection of reliable but brief qualitative and quantitative tests is needed. In this study, materials-centered and use-centered methods were chosen to evaluate the toxicology collection of the University of Saskatchewan (U of S) Library. Strengths and weaknesses of the techniques are reviewed, along with examples of their use in evaluating the toxicology collection. The monograph portion of the collection was evaluated using list checking, citation analysis, and classified profile methods. Cost-effectiveness and impact factor data were compiled to rank journals from the collection. Use-centered methods such as circulation and interlibrary loan data identified highly used items that should be added to the collection. Finally, although the data were insufficient to evaluate the toxicology electronic journals at the U of S, a brief discussion of three initiatives that aim to assist librarians as they evaluate the use of networked electronic resources in their collections is presented.

Book Selection↗

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↗

PubMed1999

[Pitfalls in the interpretation of toxicologic analysis of psychoactive substances].

Toxicological examination of biological samples of a certain case is a complex task which demands knowledge not only of modern analytical methods but also of the fate and effects of xenobiotics in organism. The evidence of unknown drugs and poisons in biological material is a difficult matter due to the broad variety of harmful substances and their unlimited possible mixtures, due to variable concentrations in a broad unpredictable range. In toxicology, there is the important question of the completeness of evidence and correctness of chemical identification of individual substances. Generally, the validation of qualitative methods is less developed than the validation of quantitative methods. The evidence of unknown harmful substances in biological samples requires often the individual consideration about optimal attitude to a nonstandard toxicological case and prevent from application of uniform procedures in fixed combinations.

Forensic Medicine↗

PubMed2002

[DNA chip technology and its application in toxicology [correction of toxiology]].

DNA chip is a new molecular biology technology rapidly developed in recent years. It fixes thousands of oligonucleotide on a silicon chip of 1 cm2, hybridizes the measuring materials marked with fluorescein or isotope with probe in DNA chip, and gets the fluorescent signal of hybridized probe through the scan of confocalmicroscope. This technology has been extensively used in HGP, DNA sequencing, transcript analysis, gene diagnosis etc. Toxicology is an important branch of life science. DNA chip can be extensively used in the toxicological [correction of toxiological] field. This paper reviewed the DNA chip technology in mechanism, manufacturing method, signal check, advantages and application prospect in toxicology.

Aerospace Medicine↗

PubMed1993

NTP Toxicology and Carcinogenesis Studies of 2,3-Dibromo-1-Propanol (CAS No. 96-13-9) in F344/N Rats and B6C3F1 Mice (Dermal Studies).

2,3-Dibromo-l-propanol, a colorless liquid, has been used as a flame retardant, as an intermediate in the preparation of the flame retardant tris(2,3-dibromopropyl) phosphate, and as an intermediate in the manufacture of pesticides and pharmaceutical preparations. Toxicology and carcinogenicity studies were conducted by applying 2,3-dibromo-1-propanol (approximately 98% pure) in ethanol to the subscapular area of the skin of male and female F344/N rats and B6C3F1 mice 5 days per week for 16 days, 13 weeks, 48 to 51 weeks (male rats), 52 to 55 weeks (female rats), 36 to 39 weeks (male mice), or 39 to 42 weeks (female mice). Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, Drosophila melanogaster, mouse Iymphoma cells, and mouse bone marrow cells. 16-DAY STUDY IN RATS Groups of five male and five female rats received dermal applications of 0, 44, 88, 177, 375, or or 750 mg/kg 2,3-dibromo-1-propanol 5 days per week for 16 days. One male and one female receiving 750 mg/kg died before the end of the study. The mean body weight gains and final mean body weights of dosed rats were similar to those of the controls. There were no clinical findings or gross lesions associated with chemical application. 16-DAY STUDY IN MICE Groups of five male and five female mice received dermal applications of 0, 44, 88, 177, 375, or 750 mg/kg 2,3-dibromo-1-propanol 5 days per week for 16 days. Four males and one female receiving 750 mg/kg died before the end of the study. The mean body weight gains and final mean body weights of dosed mice were similar to those of the controls. There were no clinical findings or gross lesions associated with chemical application. 13-WEEK STUDY IN RATS Groups of 10 male and 10 female rats received dermal applications of 0, 44, 88, 177, 375, or 750 mg/kg 2,3-dibromo-1-propanol 5 days per week for 13 weeks. All rats survived until the end of the for 16 days. One male and one female receiving study. For rats in the 750 mg/kg groups, the mean 750 mg/kg died before the end of the study. The body weight gain was 11% lower than that of the controls for males and 13% lower for females. The mean liver weights and liver-weight-to-body-weight ratios of males receiving 375 or 750 mg/kg and of females receiving 750 mg/kg were increased. Chemical-related lesions occurred in the kidney of male rats and in the liver of female rats. The average severity of nephropathy was slightly increased in males receiving dermal applications of 750 mg/kg, while individual cell necrosis was observed in the liver of all female rats in the 750 mg/kg group. 13-WEEK STUDY IN MICE Groups of 10 male and 10 female mice received dermal applications of 0, 44, 88, 177, 375, or 750 mg/kg 2,3-dibromo-1-propanol 5 days per week for 13 weeks. Eight male mice receiving 750 mg/kg died during the study, while all female mice survived. The final mean body weights of dosed and control mice were similar. The mean liver weights and liver weight-to-body-weight ratios of males receiving 375 or 750 mg/kg and of females receiving 750 mg/kg were increased. Chemical-related lesions occurred in the liver and lung of mice. Centrilobular hepatocellular necrosis occurred in all males in the 750 mg/kg group that died during the study, while individual cell necrosis was observed in the liver of females receiving 177, 375, or 750 mg/kg. Pleomorphism of the epithelium in pulmonary bronchioles occurred with a dose related increased incidence in males and females. Necrosis of the bronchiolar epithelium was observed in males receiving 750 mg/kg. LONG-TERM STUDY IN RATS Originally planned to last for 2 years, the chronic study in rats was terminated early because of reduced survival in the high-dose groups related to chemical induced neoplasms and because of the detection of antibodies to Iymphocytic choriomeningitis virus in sentinel mice. Groups of 50 male and 50 female rats received dermal applications of 0,188, or 375 mg/kg 2,3-dibromo-1-propanol 5 days per week for 48 to 51 weeks (males) or 52 to 55 weeks (females). Su5 weeks (females). Survival, Body Weights, and Clinical Findings The survival of 375 mg/kg male and female rats was significantly lower than that of the controls (males: 50/50, 41/50,16/50; females: 48/50, 38/50, 24/50). In the 375 mg/kg groups, the final mean body weight was 23&percnt; lower than that of the controls for males and 14&percnt; lower for females. There were no chemical related clinical findings. Pathology Findings Application of 2,3-dibromo-1-propanol to the skin produced significant dose-related increases in the incidences of neoplasms at numerous sites in male and female rats. Almost all dosed rats had malignant neoplasms; only one control male and one control female had malignant neoplasms. In male rats, the incidences of benign or malignant neoplasms of the skin, nose, Zymbal's gland, oral mucosa, esophagus, and small and large intestines were significantly increased in the low- and high-dose groups, while the incidences of neoplasms of the forestomach and liver were significantly increased only in the high-dose group. Neoplasms of the kidney, vascular neoplasms of the spleen, and mesotheliomas in males occurred with a significant positive trend. In female rats, the incidences of benign or malignant neoplasms of the nose, Zymbal's gland, oral mucosa, esophagus, large intestine, and liver were significantly increased in the low- and high-dose groups, while the incidences of neoplasms of the skin, forestomach, small intestine, mammary gland, and clitoral gland were significantly increased in the high-dose group only. Neoplasms of the kidney in females occurred with a significant positive trend. LONG-TERM STUDY IN MICE Originally planned to last for 2 years, the chronic study in mice was terminated early because of the detection of antibodies to lymphocytic choriomeningitis virus in sentinel mice. Groups of 50 male and 50 female mice received dermal applications of 0, 88, or 177 mg/kg 2,3-dibromo-1-propanol 5 days per week for 36 to 39 weeks (males) or 39 to 42 weeks (females). Survival, Body Weights, and Clinical Findings All mice (except two low-dose females) survived until study termination. Mean body weights of control and dosed mice were similar throughout the study, and there were no clinical findings attributed to 2,3-dibromo-l-propanol. Pathology Findings Application of 2,3-dibromo-1-propanol to the skin produced significant dose-related increases in the incidences of neoplasms at several sites in male and female mice. Benign or malignant neoplasms were observed in 40&percnt; of the low-dose males, 66&percnt; of the high-dose males, 52&percnt; of the low-dose females, and 56&percnt; of the high-dose females. In control groups, neoplasms occurred in 6&percnt; of the males and 10&percnt; of the females. In male and female mice, the incidences of benign or malignant neoplasms of the forestomach were significantly increased in the low- and high-dose groups, while the incidences of neoplasms of the skin were significantly increased only in the high-dose groups. The incidences of liver and lung neoplasms were increased in high-dose males. GENETIC TOXICOLOGY 2,3-Dibromo-l-propanol was mutagenic in a variety of short-term tests, independent of exogenous metabolic activation (S9). It induced gene mutations in three strains of Salmonella typhimurium (TA98, TA100, and TA1535) and was positive in the mouse Iymphoma assay for induction of trifluorothymidine resistance in L5178Y cells. 2,3-Dibromo-l-propanol induced sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells. In germ cells of male Drosophila melanogaster, 2,3-dibromo-1-propanol induced sex-linked recessive lethal mutations and reciprocal translocations. Results of an in vivo bone marrow micronucleus assay in male mice treated with 2,3-dibromo-1-propanol were negative. CONCLUSIONS Under the conditions of these long-term dermal studies, there was clear evidence of carcinogenic activity of 2,3-dibromo-1-propanol in male F344/N rats based on increased incidences of neoplasms of the skin, nose, oral mucosa, esophagus, forestomach, small and large intestine, Zymbal's gland, liver, kidney, tunica vaginalis, and spleen. There was clear evidence of carcinogenic activity of 2,3-dibromo-1-propanol in female F344/N rats based on increased incidences of neoplasms of the skin, nose, oral mucosa, esophagus, forestomach, small and large intestine, Zymbal's gland, liver, kidney, clitoral gland, and mammary gland. There was clear evidence of carcinogenic activity of 2,3-dibromo-1-propanol in male B6C3F1 mice based on increased incidences of neoplasms of the skin, forestomach, liver, and lung. There was clear evidence of carcinogenic activity of 2,3-dibromo-1-propanol in female B6C3F1 mice based on increased incidences of neoplasms of the skin and the forestomach. The increased incidences of alveolar/bronchiolar adenomas in female mice may have been related to chemical administration. In rats, 2,3-dibromo-1-propanol caused increased incidences of hyperkeratosis in the skin, forestomach, and esophagus, epithelial dysplasia in the nose, pleomorphism and basophilic and clear cell changes in the liver, and nuclear enlargement in the kidney. There were also chemical-related increases in the incidences of forestomach ulcers and acanthosis, angiectasis in the liver, and renal hyperplasia in male rats and epithelial dysplasia of the forestomach and bile duct hyperplasia in the liver in female rats. Chemical-related increases occurred in the incidences of hyperplasia in the skin, epithelial dysplasia of the forestomach, and bronchiolar epithelial pleomorphism and hyperplasia in male and female mice and in the incidence of eosinophilic cytoplasmic change in the liver in males. Synonyms: 2,3-dibromopropanol; 2,3-dibromopropyl alcohol.

Journal Article↗

PubMed1998

NTP Toxicology and Carcinogenesis Studies of Theophylline (CAS No. 58-55-9) in F344/N Rats and B6C3F1 Mice (Feed and Gavage Studies).

Theophylline is an alkaloid found in tea (Thea sinensis) and chocolate and is structurally related to caffeine and theobromine. Theophylline is used as a pharmaceutical agent. It stimulates the heart and central nervous system, relaxes the smooth muscles of the bronchi and blood vessels, and causes diuresis. The drug is used mainly as a bronchodilator in obstructive airway diseases, such as bronchial asthma, and for myocardial stimulation. Theophylline was nominated for toxicologic and carcinogenicity testing as a representative of the purine structural subclass, particularly because of its relationship to purines such as caffeine, 1-methyl-3-hydroxyguanine, and 3-hydroxy-1-methylxanthine, the latter two compounds having been shown to induce sarcomas in rats. Additional reasons for testing theophylline included its widespread use in humans as a pharmaceutical agent, its possible genotoxicity in vitro, and the lack of information on its potential toxicity and/or carcinogenicity under conditions of chronic oral usage. Based on reported teratogenicity and testicular toxicity, it was also recommended that reproductive studies be included in the evaluation of theophylline. The oral route of administration was selected because it is the primary route of human exposure, and the gavage route was selected because it mimics the pharmaceutical use of theophylline in humans. Male and female F344/N rats and B6C3F1 mice were given theophylline (greater than 99% pure) in feed or in corn oil by gavage for 16 days or 14 weeks or in corn oil by gavage for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, mouse bone marrow, and mouse peripheral blood. 16-DAY FEED STUDY IN RATS: Groups of five male and five female F344/N rats were given 0, 500, 1,000, 2,000, 4,000, or 8,000 ppm theophylline in feed for 16 days, which resulted in approximate daily doses of 50, 100, 250, 450, or 1,000 mg theophylline/kg body weight to males and 75, 150, 250, 450, or 1,100 mg/kg to females. All rats survived until the end of the study. The final mean body weights and body weight gains of 8,000 ppm males and females were significantly less than those of the controls. The absolute and relative testis weights of 4,000 ppm males were significantly greater than those of the controls. Increased incidences of uterine hypoplasia were observed microscopically in exposed groups of females. 16-DAY GAVAGE STUDY IN RATS: Groups of five male and five female F344/N rats were given 0, 12.5 (twice daily), 25 (once daily), 50 (once daily), 50 (twice daily), 100 (once daily), 200 (once daily), 200 (twice daily), or 400 (once daily) mg theophylline/kg body weight in corn oil by gavage. All rats receiving 400 mg/kg once daily and all but one female receiving 200 mg/kg twice daily died during the study. In groups dosed once daily, final mean body weights and body weight gains of males receiving 100 or 200 mg/kg and mean body weight gains of females receiving 50, 100, or 200 mg/kg were less than those of controls. The final mean body weights and body weight gains of groups receiving theophylline twice daily were generally similar to those of groups receiving the same daily dosages once daily. Clinical findings included rapid or labored respiration, hunched posture, and squinting. In groups dosed once daily, absolute and relative uterus weights of females receiving 100 or 200 mg/kg once daily were significantly less than those of the controls, and the absolute and relative uterus weights of females receiving 100 mg/kg once daily were significantly less than those of females receiving 50 mg/kg twice daily. Uterine atrophy was observed in three females receiving 200 mg/kg twice daily. Periarteritis of the mesenteric arteries was observed in two males and two females receiving 400 mg/kg once daily. 16-DAY FEED STUDY IN MICE: Groups of five male and five female B6C3F1 mice were given 0, 500, 1,000, 2,000, 4,000, or 8,000 ppm theophylline in feed for 16 days, resulting in approximate daily doses of 250, 475, 950, 1,800, or800, or 2,000 mg theophylline/kg body weight to males and 300, 450, 1,225, 2,000, or 4,375 mg/kg to females. All mice survived until the end of the study. Final mean body weights of 4,000 and 8,000 ppm females and mean body weight gains of 2,000, 4,000, and 8,000 ppm females were significantly greater than those of the controls. Feed consumption by exposed groups was similar to that by the controls, except that by the 8,000 ppm males, which was approximately 40&percnt; the amount of feed consumed by the control group. Histopathologic examinations were not performed due to the absence of mortality and significant exposure-related lesions. 16-DAY GAVAGE STUDY IN MICE: Groups of five male and five female B6C3F1 mice were given 0, 12.5 (twice daily), 25 (once daily), 50 (once daily), 50 (twice daily), 100 (once daily), 200 (once daily), 200 (twice daily), or 400 (once daily) mg theophylline/kg body weight in corn oil by gavage. Three males and all females receiving 400 mg/kg once daily died on day 1. There were no significant differences in final mean body weights or body weight gains. There were no histopathologic findings attributed directly to theophylline. 14-WEEK FEED STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were given 0, 1,000, 2,000, or 4,000 ppm theophylline in feed for 14 weeks, which resulted in approximate daily doses of 75, 125, or 250 mg theophylline/kg body weight to males and 75, 125, or 275 mg/kg to females. The final mean body weight of 1,000 ppm females was significantly greater than that of the control group. Feed consumption by exposed groups was similar to that by the controls. Mean cell volume and mean cell hemoglobin were significantly greater in males exposed to 2,000 or 4,000 ppm than those in the control group. Segmented neutrophil counts of all groups of exposed females were significantly greater than that of the control group. The absolute and relative kidney weights of 4,000 ppm males were significantly greater than those of the controls, and there was an exposure-related increase in the severity of nephropathy in males. Exposure-related increases in the incidences of mesenteric and/or pancreatic periarteritis were observed in males and females. 14-WEEK GAVAGE STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were given 0, 37.5, 75, or 150 mg theophylline/kg body weight in corn oil by gavage for 14 weeks. One male and one female receiving 150 mg/kg died before the end of the study. The mean body weight gain of 150 mg/kg females was significantly greater than that of the controls. Mean cell volume of 150 mg/kg males and mean cell hemoglobin of all groups of dosed males were significantly greater than those of the control group. There were slight dose-dependent increases in the incidences of mesenteric periarteritis in dosed males and females. 14-WEEK FEED STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were given 0, 1,000, 2,000, or 4,000 ppm theophylline in feed for 14 weeks, resulting in approximate daily doses of 175, 400, or 800 mg theophylline/kg body weight to males and 225, 425, or 850 mg/kg to females. All mice survived until the end of the study. The final mean body weights and body weight gains of all exposed groups of males and females were significantly less than those of the controls. Feed consumption by exposed groups was similar to that by the controls. Leukocyte, segmented neutrophil, and lymphocyte counts of 4,000 ppm males were significantly greater than those of the controls. Leukocyte and segmented neutrophil counts of 2,000 or 4,000 ppm females were significantly greater than those of the controls. There were no histopathologic findings attributed directly to theophylline exposure. 14-WEEK GAVAGE STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were given 0, 75, 150, or 300 mg theophylline/kg body weight in corn oil by gavage for 14 weeks. Three males and all females receiving 300 mg/kg, one 75 mg/kg male, and one control female died before the end of the study. Final mean body weights and body weight gains of 150 and 300 mg/kg males were significantly less than those of the controls. Mean cell volume and mean cell hemoglobin of 300 mg/kg males were significantly greater than those of the controls. There were no histopathologic findings attributed directly to theophylline treatment. 2-YEAR GAVAGE STUDY IN RATS: Groups of 50 male and 50 female rats were given 7.5, 25, or 75 mg theophylline/kg body weight in corn oil by gavage for 2 years. Survival and Body Weights: There were no significant differences in survival between dosed and control groups. Final mean body weights of all groups of dosed males and females were significantly less than those of the controls. Pathology Findings: There were no significantly increased incidences of neoplasms in dosed rats. The incidence of chronic inflammation of the mesenteric arteries was significantly increased in males receiving 75 mg/kg compared to the controls. There were doserelated negative trends in the incidences of mammary gland fibroadenoma and fibroadenoma or carcinoma (combined) in females; these differences correlated with decreased body weights. 2-YEAR GAVAGE STUDY IN MICE: Groups of 50 male B6C3F1 mice were given 0, 15, 50, or 150 mg theophylline/kg body weight and groups of 50 female B6C3F1 mice were given 0, 7.5, 25, or 75 mg/kg in corn oil by gavage for 2 years. Survival and Body Weights: Survival of 150 mg/kg males was significantly less than that of the controls. The final mean body weights of 150 mg/kg males, 25 mg/kg females, and 75 mg/kg females were significantly less than those of the control groups. Pathology Findings: There were no treatment-related increases in incidences of nonneoplastic lesions or neoplasms. In males and females, there were decreased incidences of hepatocellular adenoma and of the combined incidences of hepatocellular adenoma or carcinoma compared to the controls. Male mice had a pattern of nonneoplastic liver lesions along with silver-staining helical organisms in the liver consistent with Helicobacter hepaticus infection. The incidences of these liver lesions in 150 mg/kg males were significantly lower than those in control males. Increases in the incidences of hepatocellular neoplasms in male mice have been shown to be associated with H. hepaticus infection when hepatitis is also present. Because of this association, interpretation of the decreased incidence of liver neoplasms in male mice was more difficult. Incidences of lesions at other sites in this study were not considered to have been significantly impacted by H. hepaticus infection or its associated hepatitis. GENETIC TOXICOLOGY: Theophylline was not mutagenic in Salmonella typhimurium, with or without metabolic activation (S9). It induced sister chromatid exchanges but not chromosomal aberrations in cultured Chinese hamster ovary cells. The positive sister chromatid exchange response was noted only in the absence of S9. In vivo, a mouse bone marrow sister chromatid exchange test showed positive results at a standard 23-hour harvest time; however, this test was not repeated and the response is unconfirmed. An in vivo mouse bone marrow chromosomal aberrations test, that employed both standard and extended exposure protocols, gave negative results. The frequency of micronucleated erythrocytes was determined in peripheral blood of male and female mice exposed to theophylline in dosed feed or in corn oil by gavage for 14 weeks. No significant increases in the frequencies of micronucleated cells were seen in male or female mice in either of the studies. CONCLUSIONS: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of theophylline in male or female F344/N rats administered 7.5, 25, or 75 mg/kg. There was no evidence of carcinogenic activity of theophylline in male B6C3F1 mice administered 15, 50, or 150 mg/kg or female B6C3F1 mice administered 7.5, 25, or 75 mg/kg. Gavage administration of theophylline caused chronic inflammation of the mesenteric arteries in dosed male rats. Decreased incidences of mammary neoplasms in female rats were likely associated with lower body weights. There were dose-related decreases in the incidences of hepatocellular adenoma and hepatocellular carcinoma in male and female mice. Synonyms: 3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione; 1,3-dimethylxanthine; 1H-purine-2,6-dione; NSC 2066; pseusdotheophylline; theocin; theophyllin; theophylline, anhydrous Trade names: Accurbron; Aerobin; Aerolate III; Afonilum; Aminophylline; Aquaphyllin; Armophylline; Asmalix; Bilordyl; Bronchoretard; Bronkodyl; Cetraphylline; Constant-T; Diffumal; Duraphyl; Duraphyllin; Elixicon; Elixophyllin; Euphylline L.A.; Euphylong; LaBID; Labophylline; Lanophyllin; Lasma; Liquophylline; Optiphyllin; Parkophyllin; Phylocontin; Physpan; Pro-Vent; PulmiDur; Pulmo-Timelets; Quibron; Respbid; Rona-Phyllin; Sabidal; Slo-bid; Slo-Phyllin; Solosin; Sustaire; Tefamin; Teobid; Teofyllamin; Tesona; Theal tablets; Theo-24; Theobid; Theocap; Theochron; Theoclear; Theocontin; Theo-Dur; Theofol; Theograd; Theolair; Theolan; Theolix; Theophyl; Theoplus; Theo-Sav; Theosol; Theospan; Theostat; Theovent; TheoX; T-Phyl; Truphylline; Uni-Dur; Unifyl; Uniphyl; Uniphyllin; Xanthium

Journal Article↗

PubMed2000

NTP Toxicology and Carcinogenesis Studies of Primidone (CAS No. 125-33-7) in F344/N Rats and B6C3F1 Mice (Feed Studies).

Primidone is used alone or with other anticonvulsants in the control of grand mal, psychomotor, and focal epileptic seizures. It may control grand mal seizures refractory to other anticonvulsant therapy. Primidone was nominated by the National Cancer Institute for 2-year toxicology and carcinogenicity studies due to its human use as an anticonvulsant. Male and female F344/N rats and B6C3F1 mice received primidone (greater than 99% pure) in feed for 14 days, 14 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse bone marrow cells. 14-DAY STUDY IN RATS: Five male and five female rats were exposed to 0, 1,250, 2,500, 5,000, 10,000 or 20,000 ppm primidone (equivalent to average daily doses of approximately 120, 240, 500, 970, or 1,100 mg primidone/kg body weight to males and 120, 240, 500, or 900 mg/kg to females) in feed for 14 days. All 20,000 ppm females died before the end of the study as did one 10,000 ppm male and two 20,000 ppm males. The mean body weights of 10,000 ppm males and females and 20,000 ppm males were significantly less than those of the controls. Feed consumption by all exposed rats was generally similar to that by the controls. Males and females in the 10,000 and 20,000 ppm groups were observed to have eye discharge, ataxia, and abnormal posture and were thin and lethargic. 14-DAY STUDY IN MICE: Five male and five female mice were exposed to 0, 625, 1,250, 2,500, 5,000 or 10,000 ppm primidone (equivalent to average daily doses of approximately 100, 200, 400, or 800 mg/kg body weight to males and 100, 250, 500, or 900 mg/kg to females) in feed for 14 days. All mice in the 10,000 ppm groups and one male and one female mouse in the 5,000 ppm groups died on day 3 of the study. The mean body weights of mice in the 625, 1,250, 2,500, and 5,000 ppm groups were similar to those of the controls. Feed consumption by all exposed mice was generally similar to that by the controls. Males and females in the 10,000 ppm groups were observed to have abnormal posture, ataxia, and lethargy. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to 0, 300, 600, 1,300, 2,500, or 5,000 ppm primidone (equivalent to average daily doses of approximately 20, 40, 100, 200, or 400 mg/kg) in feed for 14 weeks. All rats survived to the end of the study. The mean body weights of male and female rats in the 2,500 and 5,000 ppm groups were significantly less than those of the controls. Feed consumption by all exposed rats was generally similar to that by the controls. A minimal to mild exposure-related thrombocytosis occurred on day 22 and at week 14 in all exposed groups of male rats and in females in the 1,300 ppm or greater groups. A minimal decrease in hemoglobin concentration occurred in 2,500 and 5,000 ppm male and female rats on day 22 and at week 14. The incidences of centrilobular hepatocyte hypertrophy in male rats exposed to 600 ppm or greater and in female rats exposed to 1,300 ppm or greater were significantly greater than those in the controls. The severity of chronic nephropathy in male rats exposed to 1,300 ppm or greater increased with increasing exposure concentration. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to 0, 300, 600, 1,300, 2,500, or 5,000 ppm primidone (equivalent to average daily doses of approximately 50, 100, 200, 400, or 1,000 mg/kg to males and 60, 120, 220, 440, or 1,100 mg/kg to females) in feed for 14 weeks. Three male and two female mice in the 5,000 ppm group died during week 1 of the study. The final mean body weights of all exposed groups were similar to those of the controls. Feed consumption by male mice in the 5,000 ppm group was slightly greater than that by the controls; this may have been due to feed spillage. Male and female mice in the 5,000 ppm groups were ataxic and lethargic. Compared to controls, the estrous cycle lengths of females exposed to 1,300, 2,500, or 5,000 ppm were significantly longer. The liver weights of male and female mice exposed to 600 po 600 ppm or greater were significantly greater than those of the controls. The incidences of centrilobular hepatocyte hypertrophy in all exposed males and in females exposed to 600 ppm or greater and the incidences of cytoplasmic alteration of the adrenal gland and hematopoietic cell proliferation of the spleen in 2,500 and 5,000 ppm males and in 5,000 ppm females were significantly greater than in the controls. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female F344/N rats were exposed to 0, 600, 1,300, or 2,500 ppm primidone (equivalent to average daily doses of approximately 25, 50, or 100 mg/kg) in feed for 2 years. Survival, Body Weights, and Feed Consumption Survival of the 1,300 and 2,500 ppm males was sig nificantly less than that of the controls. The mean body weights of males and females in the 2,500 ppm groups were less than those of the controls, beginning at week 29 for males and week 17 for females; the mean body weights of 1,300 ppm males and females were less than those of the controls during the second year of the study. Feed consumption by all exposed groups of rats was generally similar to that by the controls. Pathology Findings Male rats exposed to primidone had increased inci dences of thyroid gland follicular cell neoplasms (adenoma and/or carcinoma). All exposed groups of male rats had follicular cell adenomas or carcinomas (combined) at incidences above the historical control range, with the highest incidence in the 1,300 ppm group. Hepatocyte cytoplasmic vacuolation and centrilobular hypertrophy were associated with primidone exposure in male and female rats. These changes were more severe in females than in males and the incidences in all exposed groups of females were significantly greater than those in the controls. Females in the 2,500 ppm group had an increased incidence of hepatocellular eosinophilic foci. In 2,500 ppm males, the incidence of renal tubule hyperplasia was greater than that in the controls in the standard evaluation. Additional hyperplasias were found in the extended evaluation, and the incidences in exposed groups of males were significantly greater than that in the controls. In the extended evaluation, the incidence of renal tubule adenoma in 2,500 ppm males was significantly increased. The incidence of adenoma or carcinoma (combined) in 2,500 ppm males in the combined standard and extended evaluations were marginally increased over those in the controls. Male rats had an exposure-related increase in the severity of chronic nephropathy, which probably accounted for the reduced survival in the 1,300 and 2,500 ppm groups. The incidences of kidney cysts were increased in 1,300 and 2,500 ppm males. Hyperparathyroidism, secondary to the loss of renal function, was present in many exposed male rats. The incidences of parathyroid gland hyperplasia in all groups of exposed males were significantly greater than that in the controls. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to dietary levels of 0, 300, 600, or 1,300 ppm primidone (equivalent to average daily doses of approximately 30, 65, or 150 mg/kg to males and 25, 50, or 100 mg/kg to females) in feed for 2 years. Survival, Body Weights, Feed Consumption, and Clinical Findings Survival of the 1,300 ppm males was significantly less than that of the controls. During the second year of the study, the mean body weights of 1,300 ppm male and female mice were less than those of the controls. The final mean body weights of 600 ppm males and females were less than those of the controls. Feed consumption by all exposed groups of mice was similar to that by the controls. During the latter part of the study, a treatment-related increase in the number of animals with swelling of the abdominal area was observed; necropsy revealed that the swelling was due to liver nodules/masses. Pathology Findings The liver was a target organ in both male and female mice. The incidences and multiplicities of hepatocellular neoplasms (hepatocellular adenoma, hepatocellular carcinoma, and hepatoblastoma) in all exposed groups of males and females (except hepatoblastoma in females) were significantly greater than those in the controls. The incidences of hepatocellular adenoma or carcinoma (combined) and hepatocellular adenoma, hepatocellular carcinoma, or hepatoblastoma (combined) in all exposed groups exceeded the historical control ranges in 2-year NTP studies. The incidences of centrilobular hepatocyte hypertrophy were increased in exposed groups of males and females, and the severities increased with increasing exposure concentration. The incidences of cytoplasmic vacuolization were increased in all exposed groups of females and in 300 ppm males. Incidences of eosinophilic focus in all exposed groups of females were significantly greater than those in the controls. Proliferative changes occurred in the thyroid gland in an exposure-related manner in male and female mice. Incidences of follicular cell hyperplasia were increased in all exposed groups of males and in 600 and 1,300 ppm females, but incidences of follicular cell adenomas were increased only in male mice. GENETIC TOXICOLOGY: Primidone was mutagenic in Salmonella typhimurium strain TA1535 in the absence of S9 activation only; no mutagenicity was detected in strain TA98, TA100, or TA1537, with or without S9. Primidone did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells, with or without S9. The single in vivo study with primidone, a mouse bone marrow micronucleus test, also gave negative results. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was equivocal evidence of carcinogenic activity of primidone in male F344/N rats based on a marginal increase in thyroid gland follicular cell neoplasms, primarily adenomas, and a marginal increase in renal tubule neoplasms. There was no evidence of carcinogenic activity of primidone in female F344/N rats exposed to 600, 1,300, or 2,500 ppm. There was clear evidence of carcinogenic activity of primidone in male B6C3F1 mice based on the increased incidences of hepatocellular neoplasms, and the increased incidence of thyroid gland follicular cell adenomas was also considered to be chemical related. There was clear evidence of carcinogenic activity of primidone in female B6C3F1 mice based on the increased incidences of hepatocellular neoplasms. Exposure of rats to primidone resulted in increased incidences of hepatocyte cytoplasmic vacuolization and centrilobular hypertrophy in males and females and eosinophilic foci in females. The increased severity of nephropathy and increased incidence of renal tubule hyperplasia in male rats were related to primidone exposure. Exposure of male mice to primidone resulted in hepatocyte centrilobular hypertrophy and thyroid gland follicular cell hyperplasia. Exposure of female mice to primidone resulted in hepatocyte centrilobular hypertrophy and cytoplasmic vacuolization, eosinophilic focus, and thyroid gland follicular cell hyperplasia. Synonyms: 5-Aethyl-5-phenyl-hexahydropyrimidin-4,6-dion; 2-deoxyphenobarbital; 2-desoxyphenobarbital; desoxyphenobarbitone; 5-ethyldihydro-5-phenyl-4,6 (1H,5H)-pyrimidinedione; 5-ethylhexahydro-4,6-dioxo-5-phenylphrimidine; 5-ethylhexahydro-5-phenylpyrimidine-4,6-dione; 5-ethyl-5-phenylhexahydropyrimidine-4,6-dione Trade names: Cyral; Hexadiona; Hexamidine; Lepimidin; Lepsiral; Majsolin; Midone; Milepsin; Misodine; Misolyne; Mizodin; Mizolin; Mylepsin; Mylepsinum; Mysedon; Mysoline; Prilepsin; Primacione; Primaclone; Primacone; Primakton; Primadon; Prysoline; Pyrimidone; ROE 101; Sertan

Journal Article↗

PubMed1999

NTP Toxicology and Carcinogenesis Studies of Isoprene (CAS No. 78-79-5) in F344/N Rats (Inhalation Studies).

Isoprene, the monomeric unit of natural rubber and naturally occurring terpenes and steroids, is primarily obtained as a by-product of naphtha cracking for ethylene production. It is emitted from plants and trees, has been detected in tobacco smoke and automobile exhaust, and was identified as a major endogenous hydrocarbon in human breath. Isoprene was selected for toxicologic evaluation because of its structural similarity to 1,3-butadiene, a potent, multi-organ, rodent carcinogen, and the potential for human exposure due to its large annual production volume. A previous 26-week inhalation study followed by a 26-week recovery period provided clear evidence of carcinogenic activity of isoprene in male B6C3F1 mice. A similar study in male F344/N rats was inconclusive. Male and female F344/N rats were exposed to isoprene (99% pure) by whole body inhalation for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, mouse bone marrow and peripheral blood cells, and rat lung fibroblasts. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female F344/N rats were exposed to 220, 700, or 7,000 ppm isoprene by inhalation, 6 hours per day, 5 days per week, for 105 weeks. Survival and Body Weights: Survival rates and mean body weights of exposed male and female rats were similar to those of the chamber controls throughout the study. Urinary Vinyl Lactic Acid - Biomarker of Exposure: At 3, 6, 12, and 18 months, the concentrations of vinyl lactic acid normalized to creatinine in the urine increased with increasing exposure concentration in all exposed groups of male and female rats; however, these increases were not proportional to isoprene exposure concentrations, indicating nonlinear metabolism over this range of exposure concentrations. Pathology Findings: Exposure-related increases in the incidences of mam mary gland fibroadenoma were observed in male rats in all groups. The incidences of fibroadenoma in 7,000 ppm males and in all groups of exposed females were significantly greater than those in the chamber control groups. The incidences of fibroadenoma in all exposed groups of males and females and of multiple fibroadenoma in 7,000 ppm males and in all groups of exposed females exceeded the historical control ranges. In addition, the finding of mammary gland carcinoma in exposed male rats was noteworthy because this neoplasm rarely occurs in control male rats. The incidences of renal tubule adenoma in 700 and 7,000 ppm males and of renal tubule hyperplasia in 7,000 ppm males were significantly greater than those in the chamber controls. The severity of kidney nephropathy was slightly increased in 7,000 ppm males when compared to chamber controls. An exposure-related increase in the incidences of interstitial cell adenoma of the testis was observed in male rats. The incidences of bilateral interstitial cell adenoma and of unilateral and bilateral interstitial cell adenoma (combined) of the testis in 700 and 7,000 ppm males were significantly greater than those in the chamber controls. The incidences of interstitial cell adenoma in 700 and 7,000 ppm males exceeded the historical control range. Several rare neoplasms including benign astrocytoma, malignant glioma, malignant medulloblastoma be nign meningeal granular cell tumor, and meningeal sarcoma were observed in the brain of exposed female rats. These neoplasms have seldom or never occurred in historical chamber controls. The incidences of splenic fibrosis in 700 and 7,000 ppm males were significantly greater than that in the chamber control group. GENETIC TOXICOLOGY: Isoprene was not mutagenic in S. typhimurium and did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells with or without exogenous metabolic activation; however, in mice, isoprene induced increases in the frequency of sister chromatid exchanges in bone marrow cells and in the frequency of micronucleated erythrocytes in peripheral blood. The cell cycle duration of proliferating bone marrow cells of mice f mice exposed to 7,000 ppm isoprene was significantly lengthened. No increases in the frequency of chromosomal aberrations were observed in bone marrow cells of male mice after 12 days of exposure to isoprene, and lung fibroblasts of male and female rats exposed to isoprene for 4 weeks showed no increase in the frequency of micronuclei. CONCLUSIONS: Under the conditions of this 2-year inhalation study, there was clear evidence of carcinogenic activity of isoprene in male F344/N rats based on increased incidences of mammary gland fibroadenoma and carcinoma, renal tubule adenoma, and testicular interstitial cell adenoma. There was some evidence of carcinogenic activity of isoprene in female F344/N rats based on increased incidences and multiplicity of mammary gland fibroadenoma. A low incidence of rare brain neoplasms in exposed female rats may have been due to exposure to isoprene. Exposure to isoprene by inhalation for 2 years resulted in increased incidences of renal tubule hyperplasia and splenic fibrosis in male rats. Synonyms: Isopentadiene; b-methylbivinyl; 2-methyl-1,3-butadiene

Journal Article↗

PubMed1997

NTP Toxicology and Carcinogenesis Studies of t-Butylhydroquinone (CAS No. 1948-33-0) in F344/N Rats and B6C3F(1) Mice (Feed Studies).

t -Butylhydroquinone is used as an antioxidant in cosmetic products such as lipsticks, eye shadows, perfumes, blushers, and skin care preparations at concentrations ranging from 0.1% to 1.0%; the chemical is also used at concentrations up to 0.02% in oils, fats, and meat products to prevent rancidity, and as a polymerization inhibitor for various polyunsaturated polyesters (CIR, 1986). t-Butylhydroquinone was nominated for toxicity and carcinogenicity testing by the Food and Drug Administration. Toxicology and carcinogenicity studies were conducted in F344/N rats and B6C3F(1) mice. Mice were exposed to t-butyl hydroquinone (99% pure) in feed for 13 weeks or 2 years. For rats, exposure to t-butylhydroquinone began in utero and continued through lactation. After weaning, pups were fed diets containing the same levels of t-butylhydroquinone as those given to their respective dams for 13 weeks or for up to 30 months. The oral route of administration was selected for these studies because t-butylhydroquinone is used as a food additive and human exposure occurs predominantly through this route. In addition to the oral route of exposure, rats were exposed prenatally because perinatal exposure to butylated hydroxytoluene (a structurally related chemical) induced hepatocellular neoplasms in rats. Genetic toxicology studies were conducted in Salmonella typhimurium and cultured Chinese hamster ovary cells in vitro and in mouse bone marrow cells in vivo. 13-WEEK STUDY IN RATS: In the perinatal exposure phase of the 13-week study, groups of 10 female rats (F(0)) were fed 0, 2,500, 5,000, 10,000, 20,000, or 40,000 ppm t-butylhydroquinone from 2 weeks prior to cohabitation until the F(1) pups were weaned. F(0) females exposed to 20,000 or 40,000 ppm did not litter. The number of pup deaths in the 5,000 and 10,000 ppm groups was greater than that in the control group, and the average number of surviving pups per litter in the 10,000 ppm group was less than that in the control group. Mean body weights of pups exposed perinatally to 5,000 or 10,000 ppm were lower than that of the controls at the time of weaning. Groups of 10 male and 10 female F(1) rats continued to receive diets containing 0, 2,500, 5,000, or 10,000 ppm t-butylhydroquinone for 13 weeks fol lowing weaning. These dietary levels corresponded to approximately 200, 400, or 800 mg t-butylhydro quinone/kg body weight (males) or 200, 400, or 750 mg/kg (females) per day. All rats survived to the end of the study. The final mean body weights of males and females in the 5,000 and 10,000 ppm groups were significantly lower than those of the controls, as was the mean body weight gain of males exposed to 10,000 ppm. However, interpretation of these findings was complicated by the significantly lower initial mean body weights of the 10,000 ppm groups. Differences in initial body weights were due to in utero exposure to t-butylhydroquinone. Feed consumption by exposed groups of rats was lower than that by controls at week 2, and feed consumption by 5,000 and 10,000 ppm males and 10,000 ppm females was slightly lower than that by controls at the end of the study. Hair discoloration in all exposed groups of rats, except females exposed to 2,500 ppm, was the only clinical observation considered related to chemical exposure. The mean spermatid count, spermatid heads per testis, and spermatid heads per gram of testis were significantly decreased in males exposed to 5,000 ppm. The estrous cycles of females exposed to 2,500 or 5,000 ppm were significantly longer than that of the controls. There were no biologically significant changes in clinical pathology parameters or in organ weights. Increased incidences of hyperplasia of the nasal respiratory epithelium were observed in males exposed to 5,000 ppm and males and females exposed to 10,000 ppm, and an increased incidence of nasal exudate was observed in males in the 10,000 ppm group. Increased incidences of pigmentation were observed in the spleen of male and female rats exposed to 5,000 or 10,000 ppm. Based on lower final mean body weights wer final mean body weights and decreased feed consumption in males and females exposed to 10,000 ppm t-butylhydroquinone, exposure concentrations selected for the long-term rat study were 1,250, 2,500, and 5,000 ppm. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were fed diets containing 0, 2,500, 5,000, 10,000, 20,000, or 40,000 ppm t-butylhydroquinone for 13 weeks. These dietary levels corresponded to approximately 440, 880, 1,950, 4,000, and 8,400 mg t-butylhydro quinone/kg body weight (males) or 500, 1,100, 2,200, 4,600, and 9,000 mg/kg body weight (females) per day. There were no exposure-related deaths. Final mean body weights and body weight gains of males and females exposed to 10,000, 20,000, or 40,000 ppm were significantly less than those of the controls. Feed consumption by exposed mice appeared to be similar to that by controls, but there was excessive scatter of feed by mice exposed to 10,000, 20,000, or 40,000 ppm. Therefore, feed consumption by male and female mice in these groups was likely less than that by controls. Significant increases in segmented neutrophil counts occurred at week 3 and at the end of the study in females exposed to 10,000 ppm and males and females exposed to 20,000 or 40,000 ppm. Left caudal, left epididymis, and left testis weights of males exposed to 10,000 or 40,000 ppm were generally significantly lower than those of the controls. The estrous cycle of females exposed to 40,000 ppm was significantly longer than that of the control group. There were no biologically significant differences in organ weights. Increased incidences and severities of mucosal hyperplasia were observed in the forestomach of males exposed to 20,000 or 40,000 ppm and in females exposed to 10,000, 20,000, or 40,000 ppm, and increased incidences of inflammation were observed in the nose and skin of males and females exposed to 10,000, 20,000, or 40,000 ppm. Increased incidences of hyperplasia also occurred in the skin of males and females exposed to 10,000, 20,000, or 40,000 ppm. Based on lower final mean body weights, increased incidences of inflammation of the nose and skin, increased incidences of forestomach mucosal hyperplasia, and increased severity of nonneoplastic lesions observed in mice exposed to 10,000, 20,000, or 40,000 ppm, exposure concentrations selected for the 2-year study were 1,250, 2,500, and 5,000 ppm. LONG-TERM STUDY IN RATS: In the perinatal exposure phase of the long-term study, groups of 60 female F(0) rats were fed diets containing 0, 1,250, 2,500, or 5,000 ppm t-butyl hydroquinone, beginning 2 weeks prior to cohabitation and continuing until F(1) pups were weaned. Following weaning, groups of 70 male and 70 female F(1) rats continued to receive diets containing 0, 1,250, or 5,000 ppm, and groups of 68 male and 68 female rats continued to receive diets containing 2,500 ppm. The duration of dosing in feed was 123 weeks post-weaning for males and 129 weeks for females. These exposure concentrations resulted in daily doses of approximately 50, 100, and 200 mg t-butylhydro quinone/kg body weight (males) or 60, 120, and 240 mg/kg (females). Ten male and ten female F(1) rats from each exposure group were evaluated at 3 months. Survival, Body Weights, Feed Consumption, and Clinical Findings: Survival of females exposed to 5,000 ppm was significantly greater than that of the control group. The mean body weights of males and females exposed to 5,000 ppm were generally less than those of the controls throughout the study. Feed consumption by exposed groups was similar to that by controls. Clinical findings of hair discoloration in exposed groups of males and females were considered to be related to chemical exposure. Pathology Findings: No increased neoplasm incidences in male or female rats were attributed to t-butylhydroquinone exposure. The incidences of mammary gland fibroadenoma and fibroadenoma or adenoma (combined) were significantly decreased in males exposed to 1,250 ppm and in all exposed groups of females; and combined incidences of mammary gland fibroadenoma, adenoma, or carcinoma were significantly decreased in all groups of exposed females. The decreases occurred with significant negative trends. Incidences of renal cysts and inflammation were generally increased in exposed groups of male rats. 2-YEAR STUDY IN MICE: Groups of 60 male and 60 female mice received 0, 1,250, 2,500, or 5,000 ppm t-butylhydroquinone in feed for 104 to 105 weeks. These exposure concentrations resulted in daily doses of approximately 150, 300, or 600 mg t-butylhydroquinone/kg body weight (males) or 150, 300, or 700 mg/kg (females). As many as 10 males and 10 females from each exposure group were evaluated at 15 months. Survival, Body Weights and Feed Consumption: Survival of all exposed groups of males and females was similar to that of the control groups. Mean body weights of the 5,000 ppm groups were generally lower than those of the control groups from week 13 until the end of the study. Feed consumption by exposed groups of males and females was similar to that by the controls. There were no biologically significant differences in clinical pathology parameters between control and exposed groups of mice. Pathology Findings: No increased incidences of neoplasms or nonneoplastic lesions in male or female mice were considered to be related to t-butylhydroquinone exposure. GENETIC TOXICOLOGY: t-Butylhydroquinone was not mutagenic in any of four strains of Salmonella typhimurium, with or without liver S9 metabolic activation enzymes. It did, however, induce sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells in the presence, but not the absence, of S9. No increase in the frequency of micronucleated erythrocytes was observed in bone marrow of male mice treated with t-butylhydroquinone. CONCLUSIONS: Under the conditions of this long-term feed study, there was no evidence of carcinogenic activity of t-butylhydroquinone in male or female F344/N rats exposed to 1,250, 2,500, or 5,000 ppm. Under the conditions of this 2-year feed study, there was no evidence of carcinogenic activity of t-butylhydroquinone in male or female B6C3F(1) mice exposed to 1,250, 2,500, or 5,000 ppm. Exposure of rats to t-butylhydroquinone in feed resulted in decreased incidences of mammary gland neoplasms in males and females. Synonyms: Tert-butyl-hydroquinone; 2-(1,1-dimethylethyl)-1,4-benzenediol; 2-tert-butylhydroquinone; mono-tert-butylhydroquinone; tert-butyl-1,4-benzenediol: mono-tertiarybutylhydroquinone; 2-tert-butyl-1,4-benzenediol; 2-(1,1-dimethyl)hydroquinone; 2-(tert-butyl)-p-hydroquinone; TBHQ; MTBHQ Trade Names: Sustane; Tenox TBHQ; Banox 20BA

Journal Article↗

PubMed1997

NTP Toxicology and Carcinogenesis Studies of Salicylazosulfapyridine (CAS No. 599-79-1) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Salicylazosulfapyridine is widely used for the treatment of ulcerative colitis and Crohn's disease. It has been beneficial in the treatment of psoriasis and rheumatoid arthritis, and it has been used in veterinary medicine for the treatment of granulomatous colitis. Salicylazosulfapyridine was nominated for toxicity and carcinogenicity testing by the National Cancer Institute on the basis of its widespread use in humans and because it is a representative chemical from a class of aryl sulfonamides. Salicylazosulfapyridine is a suspect carcinogen because reductive cleavage of the azo linkage yields a p-amino aryl sulfonamide (sulfapyridine), and a related p-amino aryl sulfonamide (sulfamethoxazole) has been shown to produce thyroid neoplasms in rats. Toxicology and carcinogenicity studies were conducted in F344/N rats and B6C3F1 mice. Rats and mice were administered salicylazosulfapyridine (96% to 98% pure) in corn oil by gavage for 16 days, 13 weeks, or 2 years. The gavage route of administration was selected for these studies because it approximates the typical route of human exposure to the chemical. Genetic toxicology studies were conducted in vitro in Salmonella typhimurium and cultured Chinese hamster ovary cells and in vivo in rat and mouse bone marrow and mouse peripheral blood cells. 16-DAY STUDY IN RATS: Groups of five male and five female rats were administered 0, 675, 1,350, or 2,700 mg salicylazosulfapyridine/kg body weight in corn oil by gavage for 16 days excluding weekends. All rats survived to the end of the study. With the exception of the 675 mg/kg male group, the final mean body weights of all dosed groups of males and females were significantly lower than those of controls. Mean body weight gains of all dosed groups were less than those of controls. Clinical findings included ruffled fur and distended abdomens in male and female rats receiving 2,700 mg/kg. Hypothyroidism, evidenced by decreased serum triiodothyronine and thyroxine concentrations and increased thyroid-stimulating hormone concentrations, occurred in 2,700 mg/kg male and female rats. The absolute and relative thymus weights of male rats receiving,350 or 2,700 mg/kg and female rats receiving 2,700 mg/kg were significantly lower than those of controls. At necropsy, all dosed rats had enlarged cecae/large intestines. Male rats receiving 1,350 mg/kg and male and female rats receiving 2,700 mg/kg had red, enlarged thyroid glands. Chemical-related microscopic lesions were present in the forestomach, thymus, thyroid gland, and pituitary gland. Minimal to mild hyperplasia of the forestomach mucosa was present in the 1,350 and 2,700 mg/kg male and female groups. Lymphoid depletion was observed in the thymus of three male and three female rats in the 2,700 mg/kg groups. Male and female rats receiving 1,350 and 2,700 mg/kg had thyroid gland follicular cell hyperplasia and an increase in thyroid-stimulating hormone producing cells in the pars distalis of the pituitary gland. 16-DAY STUDY IN MICE: Groups of five male and five female mice were administered 0, 675, 1,350, or 2,700 mg salicylazosulfapyridine/kg body weight in corn oil by gavage for 16 days excluding weekends. There were no chemical-related deaths, and final mean body weights of dosed mice were similar to those of controls. No chemical-related clinical findings were noted for male or female mice. There were no differences in triiodothyronine, thyroxine, or thyroid-stimulating hormone concentrations between dosed and control mice. There were no biologically significant differences in absolute or relative organ weights between dosed and control male and female mice. At necropsy, male mice receiving 2,700 mg/kg had enlarged cecae/large intestines. There were no biologically significant histopathologic lesions attributed to salicylazosulfapyridine administration. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were administered 0, 84, 168.8, or 337.5 mg salicylazosulfapyridine/kg body weight in corn oil by gavage for 13 weeks. All rats survived to the end of the study. The finaludy. The final mean body weights of dosed male rats were similar to those of controls; the final mean body weights and body weight gains of dosed females were significantly lower than those of controls. No chemical-related clinical findings were noted in dosed male or female rats during the 13-week study. No significant differences in hematology or urinalysis parameters between control and dosed rats were observed. The absolute and relative right kidney weights of 337.5 mg/kg females were significantly greater than those of controls. At necropsy, some 337.5 mg/kg male rats had red, enlarged thyroid glands. Histopathologic changes were noted primarily in the thyroid gland and pituitary gland of males and females in the 337.5 mg/kg groups. The thyroid gland lesions observed were similar to those present in the 16-day study. Nine male rats receiving 168.8 mg/kg and ten male and seven female rats receiving.5 mg/kg had minimal but consistent changes in thyroid gland follicular cells. In the pituitary gland of 337.5 mg/kg males and females, the thyroid-stimulating hormone producing cells were enlarged and contained pale-staining cytoplasm and prominent Golgi complexes. Decreased serum triiodothyronine and thyroxine concentrations and increased thyroid-stimulating hormone concentration, similar to differences observed in the 16-day study, occurred in 337.5 mg/kg male rats; thyroid hormone concentrations were not affected in female rats. Sperm motility of all dosed groups of males was significantly lower than that of controls. Vaginal cytology parameters of dosed groups of females were similar to those of controls. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were administered 0, 675, 1,350, or 2,700 mg salicylazosulfapyridine/kg body weight in corn oil by gavage for 13 weeks. All mice survived to the end of the study. The final mean body weights of dosed male and female mice were similar to those of controls. The mean body weight gains of 1,350 and 2,700 mg/kg male mice were less than that of controls. No chemical-related clinical findings were noted in dosed male or female mice during the 13-week study. There was minimal evidence of a responsive anemia in mice in the 13-week study. The anemia was probably related to a methemoglobinemia. There were minimal decreases in thyroxine concentration in all dosed groups of male and female mice in the -week study. There were, however, no differences in triiodothyronine and thyroid-stimulating hormone concentrations between dosed and control animals. Absolute and relative liver weights of all groups of dosed male and female mice were significantly greater than those of controls. There were no chemical-related gross lesions. Microscopic evaluation of the liver revealed centrilobular hypertrophy in five 1,350 mg/kg and all 2,700 mg/kg male mice. The right cauda weight of the 1,350 mg/kg group and the right epididymis weights of all dose groups were significantly lower than those of controls. There was no evidence of chemical-related alteration in the vaginal cytology parameters of female mice. 2-YEAR STUDY IN RATS: Groups of 60 male and 60 female rats were administered 84, 168, or 337.5 mg salicylazosulfapyridine/kg body weight in corn oil by gavage for up to 105 weeks. Groups of 70 male and 60 female rats were administered the corn oil vehicle by gavage for up to 105 weeks. A stop-exposure group of 70 male rats was administered 337.5 mg/kg salicylazosulfapyridine in corn oil by gavage for 6 months, after which animals received the corn oil vehicle by gavage for the remainder of the 2-year study. Ten animals from the vehicle control male group and 10 animals from the 337.5 mg/kg stop-exposure group were evaluated at 6 months; animals from each core-study group were evaluated at 15 months. Survival, Body Weights, and Clinical Chemistry: Survival of 337.5 mg/kg male core-study rats was significantly lower than that of controls; survival of 84 and 168 mg/kg core-study males, all groups of dosed females, and the stop-exposure male group was similar to controls. Mean body weights of core-study males and stop-exposure males were similar to controls throughout the study. From week 45 to the end of the study, females in the 337.5 mg/kg group had mean body weights that were lower than those of controls. The serum thyroxine concentration in 337.5 mg/kg core-study males at study termination was minimally lower than that of controls; the serum thyroid-stimulating hormone, triiodothyronine, and reverse triiodothyronine concentrations of dosed males and females were similar to those of controls. Pathology Findings: Administration of salicylazosulfapyridine for 2 years was associated with transitional epithelial papilloma in the urinary bladder of male rats and may have been associated with transitional epithelial papilloma of the kidney and of the urinary bladder of female rats. Nonneoplastic effects in the urinary bladder and kidney of male and female rats and in the spleen of male rats were also observed. Dosed male and female rats had increased incidences of grossly and microscopically observed urinary bladder concretions (diagnosed grossly as calculi at necropsy); male and female rats that developed transitional epithelial papillomas of the urinary bladder had grossly observed concretions (calculi) in the urinary bladder at necropsy. The microscopic neoplastic and nonneoplastic urinary bladder and kidney effects observed in dosed male rats during the 2-year continuous study did not occur in dosed rats during the 2-year stop-exposure study, nor were there gross observations of concretions (calculi) at necropsy. The incidences of mononuclear cell leukemia in male and female rats were decreased. The thyroid gland hyperplasia seen in the -week study was not observed in the 2-year study, and there was no evidence of chemical-related thyroid gland follicular cell adenomas or carcinomas. 2-YEAR STUDY IN MICE: Groups of 60 male and 60 female mice were administered 0, 675, 1,350, or 2,700 mg salicylazosulfapyridine/kg body weight in corn oil by gavage for up to 104 weeks. Ten animals from each group were evaluated at 15 months. Survival, Body Weights,and Clinical Chemistry: Survival of all the dosed groups of male and female mice was similar to that of controls. Mean body weights of 675 and 1,350 mg/kg male and female mice were similar to controls throughout the study. From week 12 to the end of the study, 2,700 mg/kg male mice had mean body weights that were lower than those of controls. From week 14 to the end of the study, the 2,700 mg/kg female mice had mean body weights that were lower than those of controls. There were no chemical-related differences in triiodothyronine, reverse triiodothyronine, thyroxine, or thyroid-stimulating hormone concentrations between dosed and control mice at the 15-month evaluation. Pathology Findings: Exposure of mice to salicylazosulfapyridine in corn oil by gavage for 2 years was associated with increased incidences of hepatocellular neoplasms in males and females. Nonneoplastic effects in the liver and spleen were also observed in male and female mice. The incidences of forestomach squamous cell papilloma in females and forestomach hyperplasia in males and females were decreased. GENETIC TOXICOLOGY: Salicylazosulfapyridine was not mutagenic in Salmonella typhimurium strains TA97, TA98, TA100, or TA1535, and it did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells. These in vitro assays were performed with and without S9 metabolic activation enzymes. Results from in vivo mouse bone marrow chromo somal aberration tests were uniformly negative, while results of micronucleus assays performed on male or female mice exposed to salicylazosulfapyridine for periods ranging from 3 days to weeks were positive. Micronucleus tests in male mice for shorter exposure times (1 to 2 days) yielded negative or very weakly positive results. A three-treatment (72-hour exposure time) micronucleus test performed in male rats yielded equivocal results. Overall, results of these in vivo assays indicate that salicylazosulfa pyridine is capable of inducing chromosomal damage, possibly in the form of aneuploidy, in mouse bone marrow cells after multiple administrations. CONCLUSIONS: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activity of salicylazosulfapyridine in male and female F344/N rats based on increased incidences of neoplasms in the urinary tract. There was an increased incidence of transitional epithelial papilloma of the urinary bladder in males and a low incidence of rare transitional epithelial papillomas of the kidney and of the urinary bladder in females. There was clear evidence of carcinogenic activity of salicylazosulfapyridine in male and female B6C3F1 mice based on increased incidences of hepatocellular neoplasms. Increased incidences of nonneoplastic lesions of the urinary bladder and kidney in male and female rats and of the spleen in male rats were observed. Increased incidences of nonneoplastic lesions of the liver and spleen in male and female mice were observed. Decreased incidences of mononuclear cell leukemia in male and female rats were related to salicylazosulfapyridine administration. Decreased incidences of forestomach squamous cell papilloma in female mice and forestomach hyperplasia in male and female mice were related to salicylazosulfapyridine administration. Synonyms: 2-Hydroxy-5-[[4-[2-(pyridinylamino)sulfonyl]phenyl]azo]benzoic acid; 5-[p- (2-pyridylsulfamoyl)phenylazo]salicylic acid; sulfasalazine; salazosulfapyridine; 5-[4-(2-pyridylsulfamoyl)phenylazo]-2-hydroxybenzoic acid; 4-(pyridyl-2-amidosulfonyl)-3'-carboxy-4'-hydroxyazobenzene; sulphasalazine Trade names: Azopyrin, Azulfidine, Benzosulfa, Colo-Pleon, Reupirin, Salazopyrin

Journal Article↗

PubMed1996

NTP Toxicology and Carcinogenesis Studies of Isobutyl Nitrite (CAS No. 542-56-3) in F344 Rats and B6C3F1 Mice (Inhalation Studies).

Isobutyl nitrite is used to a limited extent as an intermediate in the syntheses of aliphatic nitrites. It is also an ingredient of various incenses or room odorizers and is used as a euphoric. The chemical has also been used as a jet propellant and in the preparation of fuels. Isobutyl nitrite was nominated by the Consumer Product Safety Commission to the NTP for toxicology and carcinogenicity studies because of its possible contribution to the high incidence of Kaposi's sarcoma among male homosexual acquired immune deficiency syndrome patients and because of the lack of available data on the potential carcinogenicity of isobutyl nitrite. Male and female F344/N rats and B6C3F1 mice were exposed to isobutyl nitrite (purity of 93% or greater) by inhalation for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, Drosophila melanogaster, and mouse peripheral blood. 16-DAY STUDY IN RATS: Groups of five male and five female F344/N rats were exposed to 0, 100, 200, 400, 600, or 800 ppm (approximately 420, 840, 1,700, 2,500, or 3,300 mg/m(3)) isobutyl nitrite by inhalation for 6 hours per day, 5 days per week for a total of 12 exposures during a 16-day period. All males and females exposed to 600 or 800 ppm and one 400 ppm female died on the first day of the study. Final mean body weights and mean body weight gains of 400 ppm males and females were significantly lower than those of the controls. Clinical findings observed in 400 ppm males and females included ocular discharge, lethargy, hunched posture, and rough coats. Absolute and relative lung weights of all exposed groups of males and of 200 and 400 ppm females were less than those of the controls. Chemical-related hyperplasia of the bronchial epithelium was observed in 200 and 400 ppm males and females and hyperplasia of the nasal turbinate epithelium was observed in rats exposed to 400 ppm or less. Hemosiderin pigmentation was observed in the spleen of 200 and 400 ppm males and females and bone marrow hematopoietic hyperplasia was observed in rats exposed to 400 ppm or less. 16-DAY STUDY IN MICE: Groups of five male and five female B6C3F1 mice were exposed to 0, 100, 200, 400, 600, or 800 ppm (approximately 420, 840, 1,700, 2,500, or 3,300 mg/m(3)) isobutyl nitrite by inhalation for 6 hours per day, 5 days per week for a total of 12 exposures during a 16-day period. Three males and four females exposed to 800 ppm died before the end of the study. Final mean body weights and mean body weight gains of 600 and 800 ppm males and females were significantly lower than those of the controls. Mice exposed to 400 ppm or greater were lethargic and exhibited hunched posture and rough coats. Absolute and relative lung weights of 600 and 800 ppm males and the relative lung weight of 600 ppm females were significantly greater than those of the controls. Chemical-related hyperplasia of the bronchiolar epithelium was observed in all exposed groups of males and females. Lymphocytic atrophy of the spleen and thymus was observed in males and females exposed to 400 ppm or greater. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were exposed to 0, 10, 25, 75, 150, or 300 ppm (approximately 42, 105, 315, 630, or 1,260 mg/m(3)) isobutyl nitrite by inhalation for 6 hours per day, 5 days per week for 13 weeks. All rats survived to the end of the study. Final mean body weights and mean body weight gains of 300 ppm males and females were significantly lower than those of the controls, as was the mean body weight gain of 150 ppm females. Clinical findings observed during the study included ruffled fur in 300 ppm males and females, hypoactivity in 300 ppm males, and hyperactivity in 150 and 300 ppm females. A very mild chemical-related methemoglobinemia and anemia occurred in male and female rats in the 75, 150, and 300 ppm groups. Hematopoietic hyperplasia occurred in the bone marrow of all exposed groups of males and females and was considered to be a secondary response to the anemia and methed methemoglobinemia. There was minimal hemosiderin pigment accumulation in the spleens of males and females exposed to 75 ppm or greater, mild to moderate epithelial cell hyperplasia of the nasal mucosa was observed in 300 ppm males and females, and minimal hyperplasia occurred in 150 ppm males and females. Hyperplasia of the bronchial epithelium was observed in 300 ppm males and females. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were exposed to 0, 10, 25, 75, 150, or 300 ppm (approximately 42, 105, 315, 630, or 1,260 mg/m(3)) isobutyl nitrite by inhalation for 6 hours per day, 5 days per week for 13 weeks. There were no chemical-related deaths. Final mean body weights and mean body weight gains of 150 and 300 ppm females were significantly less than those of the controls. Final mean body weights and mean body weight gains of exposed groups of males were similar to those of the controls. There were no chemical-related clinical findings. A very mild chemical-related methemoglobinemia occurred in male and female mice in the 150 and 300 ppm groups. A very mild anemia occurred in the 300 ppm groups. In the lung, increased incidences of mild to moderate hyperplasia of the bronchiolar epithelium occurred in males and females exposed to 300 ppm. Minimal hyperplasia occurred in males exposed to 75 ppm or greater and in females exposed to 150 ppm. Minimal epithelial cell hyperplasia of the nasal mucosa was observed in 300 ppm males. Increased hematopoiesis of the spleen, secondary to the hematotoxicity, occurred in males exposed to 75 ppm or greater and in females exposed to 150 or 300 ppm. Increased hemosiderosis of the spleen occurred in males exposed to 300 ppm and in females exposed to 75 ppm or greater. 2-YEAR STUDY IN RATS: Based on the low final mean body weights, anemia, and the mild to moderate nasal mucosal lesions and the hyperplastic bronchial lesions observed in 300 ppm males and females, isobutyl nitrite exposure concentrations selected for the 2-year inhalation study in rats were 37.5, 75, and 150 ppm. Groups of 56 male and 56 female rats were exposed to 0, 37.5, 75, or 150 ppm (equivalent to 0, 158, 315, or 630 mg/m(3)) isobutyl nitrite by inhalation for 6 hours per day, 5 days per week, for 103 weeks. Ten male and 10 female rats from each group were evaluated at 15 months for clinical pathology and histopathology. Survival, Body Weights, Clinical Findings, Hematology, and Clinical Chemistry: Survival rates of exposed groups of rats were greater than those of the controls, and the survival rates of 75 and 150 ppm males were significantly greater than that of the control. Mean body weights of 150 ppm males and females were 3&percnt; to 11&percnt; lower than those of the controls throughout the course of the study. There were no clinical findings considered to be related to isobutyl nitrite exposure. A very mild methemoglobinemia and anemia occurred in male and female rats exposed to 75 or 150 ppm. Pathology Findings: Incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar adenoma or carcinoma (combined) occurred with significant positive trends in exposed males and females, and the incidences of these neoplasms in 75 ppm males and in 150 ppm males and females were significantly greater than those in the controls. The incidence of alveolar/bronchiolar carcinoma was significantly greater in 150 ppm male rats than that in the controls. The incidences of alveolar epithelial hyperplasia were also increased in 75 and 150 ppm males and in all exposed groups of females. The incidences of mononuclear cell leukemia in exposed groups of males and females were significantly less than those in the controls. 2-YEAR STUDY IN MICE: Based on the low final mean body weight of 300 ppm females and the mild to moderate bronchiolar hyperplasia observed in 300 ppm males and females, isobutyl nitrite exposure concentrations selected for the 2-year inhalation study in mice were 37.5, 75, and 150 ppm. Groups of 60 male and 60 female mice were exposed to 0, 37.5, 75, or 150 ppm (equivalent to 0, 158, 315, or 630 mg/m(3)) isobutyl nitrite by inhalation for 6 hours per day, 5 days per week, for 103 weeks. As many as 10 male and 10 female mice from each group were evaluated at 15 months for clinical pathology and histopathology. Survival, Body Weights, Clinical Findings, and Hematology and Clinical Chemistry: Survival rates of exposed groups of males were similar to those of the controls. Survival rates of exposed groups of females were greater than those of the controls, and the survival rate in 37.5 ppm females was significantly greater than that of the controls. Mean body weights of exposed groups of males and of 37.5 and 75 ppm females were similar to those of the controls throughout the study. Mean body weights of 150 ppm females were lower than those of the controls from week 20 until the end of the study. There were no biologically significant clinical findings noted in the 2-year study in mice. A very mild methemoglobinemia and anemia occurred in male and female mice exposed to 75 or 150 ppm. Pathology Findings: Incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar adenoma or carcinoma (combined) occurred with significant positive trends in exposed males and females, and the incidences of these neoplasms were significantly greater than those in the controls in 75 ppm males and in 150 ppm males and females. Incidences of alveolar epithelial hyperplasia were significantly increased in 75 and 150 ppm male and female mice. Thyroid gland follicular cell adenoma occurred with a significant positive trend in male mice; the incidences of thyroid gland follicular cell hyperplasia were increased in all exposed groups of males, and the incidences in males exposed to 37.5 or 150 ppm were significantly greater than those in the controls. Incidences of serous exudate and olfactory epithelium atrophy in the nose of 150 ppm females were significantly greater than those in the controls. Incidences of minimal to mild hemosiderin pigment in the spleen of 75 and 150 ppm male mice were significantly greater than those in the controls. GENETIC TOXICOLOGY: Isobutyl nitrite was found to be mutagenic in vitro and in vivo. It induced base-pair substitution mutations in Salmonella typhimurim strains TA100 and TA1535 and sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells. Positive responses in the S. typhimurium tests required S9 activation, but isobutyl nitrite induced chromosomal effects in cultured Chinese hamster ovary cells with and without S9. In vivo, no induction of sex-linked recessive lethal mutations was noted in the germ cells of male Drosophila melanogaster exposed to isobutyl nitrite via feeding or injection. However, significant increases in micronucleated normochromatic erythrocytes were observed in the peripheral blood of male and female mice treated with isobutyl nitrite for 90 days by inhalation. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was clear evidence of carcinogenic activity of isobutyl nitrite in male and female F344/N rats based on the increased incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar adenoma or carcinoma (combined). There was some evidence of carcinogenic activity of isobutyl nitrite in male and female B6C3F1 mice based on the increased incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar adenoma or carcinoma (combined) in males and females. The increased incidence of thyroid gland follicular cell adenoma in male mice may have been related to isobutyl nitrite exposure. Exposure of rats and mice to isobutyl nitrite by inhalation for 2 years resulted in increased incidences of alveolar epithelial hyperplasia (male and female rats and mice), thyroid gland follicular cell hyperplasia and splenic hemosiderin pigmentation (male mice), and serous exudate and atrophy of the olfactory epithelium of the nose (female mice). Exposure of rats to isobutyl nitrite by inhalation for 2 years resulted in decreased incidences of mononuclear cell leukemia in males and females.

Journal Article↗

PubMed1993

NTP Toxicology and Carcinogenesis Studies of Oxazepam (CAS No. 604-75-1) in Swiss-Webster and B6C3F1 Mice (Feed Studies).

Oxazepam is one of a number of benzodiazepines used therapeutically as a sedative-hypnotic and antianxiety agent. Toxicology and carcinogenesis studies were performed by administering oxazepam (greater than 99% pure) in feed to male and female Swiss-Webster and B6C3F1 mice for 14 weeks, 57 weeks (Swiss-Webster), or 2 years (B6C3F1). Neurobehavioral assessments were performed during the studies. Genetic toxicology studies were conducted in Salmonella typhimurium and cultured Chinese hamster ovary cells, and peripheral blood samples were analyzed for frequency of micronucleated normochromatic erythrocytes. Supplemental studies were performed to compare the metabolism and toxicokinetics of oxazepam in the two mouse strains, to evaluate the effect on liver cell replication rates, to perform clinical pathology assessments, and to examine the mutation spectrum and frequency of activated H-ras oncogenes in liver neoplasms from the 2-year study with B6C3F1 mice. 14-WEEK STUDY IN SWISS-WEBSTER MICE: Groups of 10 male and 10 female Swiss-Webster mice received oxazepam in feed at concentrations of 0, 625, 1,250, 5,000, 10,000 ppm for 14 weeks. One 625 ppm male and one 10,000 female were killed moribund before the end of the study, and the condition of the female mouse was attributed to oxazepam exposure. Mean body weight gains of exposed groups were similar to those of the controls. Exposed mice displayed chemical-related sedation and lethargy during the first study week, but appeared normal thereafter. In the neurobehavioral studies, reductions in grip strength were evident in both male and female mice at week 2 and persisted in males through week 11. An antianxiety effect was detected in exposed mice in measures of motor activity, startle response, and reactions to thermal stimulus. At necropsy, absolute and relative liver weights were increased in an exposure-related manner and were approximately two-fold greater in 10,000 ppm mice than in controls. Centrilobular hepatocellular hypertrophy was present only in exposed mice, and the severity increased with dose. 14-WEEK STUDY IN B6C3F1 MICE: Groups of 10 male and 10 female B6C3F1 mice received oxazepam in feed at concentrations of 0, Groups of 10 male and 10 female Swiss-Webster mice 625, 1,250, 2,500, 5,000, or 10,000 ppm for 14 weeks. received oxazepam in feed at concentrations of 0, There were no deaths that were clearly related to 625,1,250, 2,500, 5,000, or 10,000 ppm for 14 weeks. oxazepam exposure. Mean body weight gains of One 625 ppm male and one 10,000 ppm female were exposed groups were similar to those of the controls. Exposed mice displayed chemical-related sedation and lethargy during only the first study week. In neurobehavioral studies, reductions in grip strength were evident in males at week 2 but were no longer observed at week 12. An antianxiety effect was noted in exposed mice in measures of motor activity, startle response, and reactions to a thermal stimulus (females). At necropsy, absolute and relative liver weights were increased in an exposure-related manner and were approximately two-fold greater in 10,000 ppm mice than in controls. Centrilobular hepatocellular hypertrophy was present only in exposed mice, and the severity increased with dose. CHRONIC STUDIES: Groups of 60 male and 60 female Swiss-Webster and B6C3F1 mice received oxazepam in feed at concentrations of 0, 2,500, or 5,000 ppm. Additional groups of 60 male and 60 female B6C3F1 mice received 125 ppm in feed to allow for study of a group with projected serum concentrations of oxazepam similar to those achieved in humans taking a therapeutic dose. Ten male and 10 female B6C3F1 mice per group were evaluated at 15 months. Average daily oxazepam consumption varied throughout the studies, and the overall daily average ranged from 10 to 29 mg/kg body weight for the 125 ppm groups, 234 to 512 mg/kg for the 2,500 ppm groups, and 444 to 1,085 mg/kg for the 5,000 ppm groups. Serum oxazepam concentrations determined at 57 weeks in Swiss-Webster mice and at the 15-month interim evaluation of B6C3F1 mice 1 mice were approximately 1 ug/mL in the 125 ppm groups, 4 to 7 μg/mL in the 2,500 ppm groups, and 7 to 10 μg/mL in the 5,000 ppm groups. Neurobehavioral assessments during the chronic studies of each strain of mice were confounded by the poor survival and deteriorating condition of mice with hepatic neoplasia. However, within the limitations of the studies, there were no notable changes in the types of behaviors observed compared to those observed in the 14-week studies, nor was there an enhancement in the degree to which they were exhibited. 57-Week Study in Swiss-Webster Mice: Survival, Body Weights, Feed and Compound Consumption, and Clinical Findings: At 57 weeks, survival of exposed mice was significantly lower than that of controls (males: O ppm, 45/60; 2,500 ppm, 19/60; 5,000 ppm, 10/60; females: 47/60, 28/59, 17/59), causing the study to be terminated. Mean body weights of exposed males were similar to controls until week 17; afterwards, mean body weights of exposed male groups were lower than those of controls. Final mean body weights of exposed males were 9% lower than that of the controls. The mean body weight of 2,500 ppm females was greater than that of the controls throughout the study. Females receiving 5,000 ppm had a mean body weight greater than that of the controls early in the study; after week 29, the mean body weight of this group was similar to that of the controls. Feed consumption by exposed males and females was slightly lower than that by the controls, and females in all groups, including controls, consumed slightly more feed than males throughout the study. Dietary levels of 2,500 and 5,000 ppm oxazepam resulted in average daily compound consumption levels of 270 and 570 mg/kg for males and 320 and 670 mg/kg for females. Hypoactivity and sedation were observed in exposed mice during the first week of the study. There were no other clinical findings associated with oxazepam exposure. Pathology Findings: Systemic amyloidosis was the principal cause of death in mice dying before the study was terminated. The lower survival of mice receiving oxazepam was attributed to an increase in the extent and severity of amyloid deposits in many organs, including the heart and kidney. Atrial thrombosis and pulmonary lesions consistent with chronic heart failure occurred at higher incidences and with greater severity in exposed mice. The incidence of hepatocellular adenomas (males: 1/60, 35/60, 50/60; females: 0/60, 22/59, 47/59) and carcinomas (males: 0/60, 5/60,19/60; females: 1/60, 1/59, 11/59) were increased in exposed mice. The incidences of eosinophilic foci were also increased in exposed mice (males: 0/60, 22/60, 22/60; females: 0/60, 20/59, 14/59), and there was evidence of increased centrilobular hepatocyte hypertrophy (males: 12/60, 46/60, 47/60; females: 3/60, 51/59, 53/59). 2-Year Study in B6C3F1 Mice: Survival, Body Weights, Feed and Compound Consumption, and Clinical Findings: Survival of mice receiving 2,500 and 5,000 ppm was significantly lower than that of controls (males: O ppm, 45/50; 125 ppm, 44/50; 2,500 ppm, 15/50; 5,000 ppm, 0/50; females: 39/50, 41/50, 2/50, 0/50). Mean body weight gains of exposed male and female mice were similar to controls until about week 15 when weight gains for mice exposed to 2,500 or 5,000 ppm slowed in relation to controls, resulting in weight gains approximately 30&percnt; to 40&percnt; lower than those of the controls throughout the remainder of the study. Mean body weight gain of male mice exposed to 125 ppm was similar to that of the controls, while that of female mice receiving 125 ppm was 10&percnt; to 15&percnt; lower than that of the controls after about week 45. Feed consumption by exposed males and females was similar to that by controls. Dietary levels of 125, 2,500, and 5,000 ppm resulted in average daily oxazepam consumption levels of 12, 310, and 690 mg/kg body weight for males and 15, 350, and 780 mg/kg for females. In the 5,000 ppm groups, lethargy and sedation were observed in a few mice during the first week of study. Pathology Findings: The early deaths of many of the B6C3F1 mice exposed to oxazepam were attributed to a marked increase in the incidences of hepatoblastoma (males: 0/49, 2/50, 21/50, 13/50; females: 0/50, 1/50, 8/50, 8/50), hepatocellular adenoma (males: 17/49,18/50, 34/50, 32/50; females: 25/50, 35/50, 35/50, 36/50), and hepatocellular carcinoma (males: 9/49, 5/50, 45/50, 50/50; females: 9/50, 5/50, 49/50, 44/50). Moderate hypertrophy of centrilobular hepatocytes occurred in mice receiving 2,500 and 5,000 ppm (males: 0/49, 2/50, 26/50, 43/50; females: 0/50, 2/50,11/50, 29/50). An increase in the incidence of follicular cell hyperplasia of the thyroid gland occurred in all exposed groups of mice (males: 4/49, 22/50, 49/50, 47/50; females: 16/50, 34/50, 49/50, 44/50), and thyroid gland follicular cell adenoma was increased in exposed females (0/50, 4/50, 5/50, 6/50). Testicular atrophy occurred in the 2,500 and 5,000 ppm groups (1/50, 0/50, 25/50, 38/50), and the incidence of epididymal Iymphocyte infiltration was increased in all exposed groups (2/50,14/50, 33/50, 21/50). The frequency of hepatocellular neoplasms with an activated H-ras oncogene in the B6C3F1 mice and the mutation spectrum of the H-ras gene were determined. The mutation spectrum of the H-ras genes in the relatively few neoplasms from exposed mice that did have an activated H-ras did not differ from the spectrum of mutations observed in neoplasms from controls, but the proportion of neoplasms with an activated H-ras gene decreased with increasing oxazepam dose. While 11 of 19 (58&percnt;) neoplasms from control mice had an activated H-ras gene, only 1 of 40 neoplasms from mice receiving 2,500 or 5,000 ppm oxazepam exhibited a similar molecular lesion. Thirteen of 37 (35&percnt;) neoplasms from mice in the 125 ppm group had an activated H-ras oncogene, suggesting that, although the incidence of all liver neoplasms was not statistically increased compared to controls, there was an increase in a similar subset of neoplasms (lacking an activated H-ras) that occurred with increased incidence at higher doses. SUPPLEMENTAL STUDIES: Because exposure to oxazepam caused increased incidences of liver neoplasms, supplemental short-term studies were performed. Oxazepam given in feed to male B6C3F1 mice at 25, 125, 2,500, or 5,000 ppm for up to 13 weeks was found to cause a dose-related increase in nuclear labeling index in studies measuring the incorporation of bromodeoxyuridine into replicating liver cells. This increase was statistically significant at all but the 25 ppm exposure level and was limited to mice evaluated at 15 days. Cell replication rates in most groups evaluated at 30 days and after were similar to control rates. There was minimal evidence suggestive of hepatocyte necrosis either by light microscopy or in clinical chemistry measures. There was, however, evidence of cholestasis, likely due to physical obstruction of bile canaliculi by swollen hepatocytes. The metabolic fate and toxicokinetics of oxazepam were evaluated in each strain of mice and were compared to published data from human studies. Both mice and humans form glucuronides of oxazepam and form 3- and 4-hydroxy and methoxy derivatives of the phenyl group. Oxidative metabolism of the phenyl group appears to be more prevalent in mice than is reported for humans. Elimination half-lives of parent compound do not differ between Swiss-Webster and B6C3F1 mice and are similar to values reported for humans. GENETIC TOXICOLOGY: Oxazepam was not mutagenic in any of several strains of Salmonella typhimurium, nor did it induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells. These in vitro tests were performed with and without S9 metabolic activation. Results from an in vivo mouse peripheral blood micronucleus test performed on the B6C3F1 mice used in the 14-week study were also negative. CONCLUSIONS: Under the conditions of these feed studies, there was clear evidence of carcinogenic activity of oxazepam in male and female Swiss-Webster mice based on increased incidences of hepatocellular adenoma and carcinoma. There was clear evidence of carcinogenic activity of oxazepam in male and female B6C3F1 mice based on increased incidences of hepatoblastoma and hepatocellular adenoma and carcinoma. Increased incidences of hyperplasia of thyroid gland follicular cells in male and female B6C3F1 mice and of follicular cell adenomas in female B6C3F1 mice were also related to oxazepam exposure. Administration of oxazepam to Swiss-Webster mice resulted in centrilobular hepatocellular hypertrophy and increased incidences and severity of systemic amyloidosis. Administration of oxazepam to B6C3F1 mice also resulted in centrilobular hepatocellular hypertrophy. Synonyms: 7-Chloro-1,3-dihydro-3-hydroxy-5-phenyl-2 H - 1,4-benzodiazepin-2-one Trade Names: Tazepam, Wy-3498, Serax

Journal Article↗

PubMed1995

NTP Toxicology and Carcinogenesis Studies of Methylphenidate Hydrochloride (CAS No. 298-59-9) in F344/N Rats and B6C3F1 Mice (Feed Studies).

Methylphenidate hydrochloride is a drug used in the treatment of narcolepsy and attention deficit hyperactivity disorders. This drug was nominated for study by the Food and Drug Administration and the National Cancer Institute because of its widespread use in human medicine and because of lack of data on its potential carcinogenicity. Oral administration is the most common route of human exposure. Toxicology and carcinogenicity studies were conducted by administering methylphenidate hydrochloride (USP grade) ad libitum in feed to groups of male and female F344/N rats and B6C3F1, mice for 14 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and in cultured Chinese hamster ovary cells. 14-DAY STUDY IN RATS: Groups of five male and five female F344/N rats were fed diets containing 0, 16, 62, 250, 1,000, or 4,000 ppm methylphenidate hydrochloride for 14 days. All rats survived to the end of the study. The final mean body weights of 4,000 ppm male and female rats were 9% lower than those of the controls. Absolute and relative liver weights of 4,000 ppm males and females were significantly greater than those of the controls. Clinical findings during the first week of the study included hyperactivity in 4,000 ppm males and females, but these animals appeared to be normal during the second week of treatment. No treatment-related gross lesions were observed; however, centrilobular hypertrophy was observed in 4,000 ppm males and females. 14-DAY STUDY IN MICE: Groups of five male and five female B6C3F1, mice were fed diets containing 0, 16, 62, 250, 1,000, or 4,000 ppm methylphenidate hydrochloride for 14 days. Three 4,000 ppm males died during the second week of the study; all other mice survived to the end of the study. The final mean body weight of 4,000 ppm females was 11% lower than that of the controls, and the mean body weight gains of 1,000 and 4,000 ppm males and females were also significantly lower than those of the controls. Absolute and relative liver weights of all exposed groups of males and of 4,000 ppm females were significantly greater than those of the controls. Hyperactivity was observed during the second week of the study in some 4,000 ppm males. Degeneration and necrosis of the renal tubule epithelium were observed in two 4,000 ppm males. Hepatocellular hypertrophy was observed in males and females exposed to 1,000 or 4,000 ppm and in males exposed to 250 ppm. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were fed diets containing 0, 125, 250, 500, 1,000, or 2,000 ppm methylphenidate hydrochloride for 13 weeks. There were no chemical-related effects on survival. Mean body weight gains of 500, 1,000, and 2,000 ppm males and females and of 250 ppm females were significantly lower than those of the controls. Final mean body weights of exposed males and females were similar to those of the controls. During the first week of the study, feed consumption by 2,000 ppm rats was less than that by controls, but during the remainder of the study feed consumption by exposed and control groups was similar. Rats exposed to 125, 250, 500, 1,000, or 2,000 ppm received approximate doses of 8, 15, 30, 70, or 130 mg methylphenidate hydrochloride per kilogram body weight per day (males) or 9, 18, 30, 70, or 150 mg/kg per day (females). Clinical findings in 1,000 and 2,000 ppm females included slight hypersensitivity to touch, hyperactivity, and increased vocalization during handling periods. Absolute and relative liver weights of 2,000 ppm males and females were significantly greater than those of the controls, as were the relative liver weights of 1,000 ppm males and females. No chemical-related differences in bone length, bone density, or nose-to-rump lengths were noted in males or females, nor were there treatment related histopathologic lesions. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1, mice were fed diets containing 0, 125, 250, 500, 1,000, or 2,000 ppm methylphenidate hydrochloride for 13 weeks. There were no chemical-related effects on ed effects on survival. Final mean body weights of males exposed to 250, 500, 1,000, or 2,000 ppm and of 2,000 ppm females were significantly lower than those of the controls. The final mean body weights of other exposed male and female groups were similar to those of the controls. During the first week of the study, feed consumption by 2,000 ppm mice was less than that by controls; feed consumption by exposed groups was similar to that by the controls throughout the remainder of the study. Mice exposed to 125, 250, 500, 1,000, or 2,000 ppm received approximate doses of 15, 30, 70, 115, or 230 mg/kg per day (males) or 15, 30, 70, 125, or 260 mg/kg per day (females). No chemical-related clinical findings were observed. Absolute and relative liver weights of 1,000 and 2,000 ppm males and females were significantly greater than those of the controls, as were the relative liver weights of 125, 250, and 500 ppm males. Centrilobular hypertrophy and hepatocellular degeneration or necrosis were observed in males exposed to 500, 1,000, or 2,000 ppm methylphenidate hydrochloride. 2-YEAR STUDY IN RATS: Based on the increased liver weights and lower body weight gains in 2,000 ppm rats in the 13-week study, the high dose selected for the 2-year rat study was 1,000 ppm. Groups of 70 male and 70 female F344/N rats were fed diets containing 0, 100, 500, or 1,000 ppm methylphenidate hydrochloride for up to 2 years. As many as 10 male and 10 female rats per exposure group were evaluated at 9 or 15 months. Survival, Body Weights, Feed and Compound Consumption, and Clinical Findings: Survival of exposed rats was similar to that of the controls at the end of the study. Mean body weights of 500 and 1,000 ppm males were 3&percnt; to 10&percnt; lower than those of the controls from week 30 to the end of the study; during the same time period, mean body weights of 500 and 1,000 ppm females were 4&percnt; to 24&percnt; less than those of the controls. Final mean body weights of rats exposed to 100, 500, or 1,000 ppm were 102&percnt;, 95&percnt;, or 90&percnt; (males) and 96&percnt;, 89&percnt;, or 78&percnt; (females) those of the controls. Rats exposed to 100, 500, or 1,000 ppm methylphenidate hydrochloride in feed received approximate doses of 5, 25, or 50 mg/kg per day (males and females). The only chemical-related clinical finding was an increased incidence of fighting among group-housed males exposed to 1,000 ppm. Hematology and Clinical Chemistry: No biologically significant differences in hematology or clinical chemistry parameters occurred at 9 or 15 months. Pathology Findings: In female rats exposed to 500 or 1,000 ppm, the incidence of mammary gland fibroadenomas was decreased (0 ppm, 15/49; 100 ppm, 13/50; 500 ppm, 6/ 48; 1,000 ppm, 5/50), and the decrease was considered to be related to chemical administration. No significant chemical-related increases in neoplasm incidences were observed in male or female rats. 2-YEAR STUDY IN MICE: Based on the liver toxicity and lower body weight gains observed in 1,000 and 2,000 ppm mice in the 13-week study, the high dose selected for the 2-year study was 500 ppm. Groups of 70 male and 70 female B6C3F1 mice were fed diets containing 0, 50, 250, or 500 ppm methylphenidate hydrochloride for 2 years. As many as 10 male and 10 female mice per exposure group were evaluated at 9 or 15 months. Survival, Body Weights, Feed and Compound Consumption, and Clinical Findings: Survival of exposed mice was similar to that of the controls at the end of the study. Mean body weights of mice exposed to 250 or 500 ppm were 3&percnt; to 11&percnt; lower than those of the controls throughout much of the study; during the same time period, mean body weights of 250 ppm females were 3&percnt; to 7&percnt; lower than those of the controls. Final mean body weights of mice exposed to 50, 250, or 500 ppm were 97&percnt;, 89&percnt;, or 93&percnt; (males) and 98&percnt;, 93&percnt;, or 97&percnt; (females) that of the controls. Mice exposed to 50, 250, or 500 ppm methylphenidate hydrochloride in feed were estimated to have received 6, 30, or 60 mg/kg body weight per day (males) or 8, 40, or 80 mg/kg per day (females). There were no chemical related clinical findings. Hematology and Clinical Chemistry: No biologically significant differences in hematology or clinical chemistry parameters occurred at 9 or 15 months. Pathology Findings: The principal lesions associated with the administration of methylphenidate hydrochloride occurred in the liver. A few hepatocellular neoplasms were observed in control and exposed male mice at the 9-and 15-month interim evaluations, but the incidences in exposed groups were not significantly increased. At the end of the 2-year study, incidences of eosinophilic foci were increased in 500 ppm males and females. Increased incidences of hepatoblastoma occurred in 500 ppm males (0 ppm, 0/50; 50 ppm, 1/50; 250 ppm, 1/50; 500 ppm, 5/50). Increased incidences of hepatocellular adenoma also occurred in 500 ppm males (18/50, 18/50, 16/50, 29/50) and females (6/49, 10/48, 10/49, 28/50). The incidences of hepatocellular carcinoma were similar among control and exposed mice. GENETIC TOXICOLOGY: Methylphenidate hydrochloride was not mutagenic in Salmonella typhimurium strains TA97, TA98, TA100, TA1535, or TA1537, with or without exogenous metabolic activation (S9). Methylphenidate hydrochloride was also tested for induction of sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells. In the chromosomal aberrations tests, positive results were not consistently dependent upon the presence or absence of S9 activation. Sister chromatid exchanges were not increased in the presence of S9, but one laboratory did obtain a positive response without S9 by testing higher doses than were used in tests With S9. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of methylphenidate hydrochloride in male or female F344/ N rats receiving 100, 500, or 1,000 ppm. There was some evidence of carcinogenic activity of methylphenidate hydrochloride in male and female B6C3F1 mice based on the occurrence of hepatocellular neoplasms. Treatment of female rats with methylphenidate hydrochloride was associated with a decrease in the incidence of mammary gland fibroadenomas. Administration of methylphenidate hydrochloride to male and female mice resulted in increased incidences of eosinophilic foci. Synonyms: a-phenyl-2-piperidineacetic acid methyl ester hydrochloride; methylphenidylacetate hydrochloride; a-phenyl-a-(2-piperidyl)acetic acid methyl ester hydrochloride; methyl a-phenyl-a-(2-piperidyl)acetate hydrochloride

Journal Article↗