Phenylsilsesquioxane fluid: developmental toxicity studies in rats and rabbits following oral administration.

Phenylsilsesquioxane fluid (PSF) is used widely in the personal care industry and is a common component of skin and oral care products. The potential developmental toxicity of PSF was evaluated in rats and rabbits. Groups of 25 sperm-positive Sprague-Dawley rats (Taconic Farms) and 15 sperm-positive New Zealand White rabbits (HRP) were administered dose levels of 50, 500, or 1000 mg/kg PSF in corn oil. Vehicle control groups of equal size were administered corn oil alone. Rats were dosed daily (5 ml/kg) on gestation d 6-15 and sacrificed on gestation d 20, while rabbits were dosed daily (1.5 ml/kg) on gestation d 6-18 and sacrificed on gestation d 29. The fetuses were removed by cesarean section and examined for gross external, visceral, cephalic, and skeletal anomalies. No treatment-related clinical signs of toxicity were observed. No marked effects upon maternal food consumption, body weight, body weight gain, or uterus or liver weight were detected. Fetal viability and body weight, as well as developmental endpoints, were unaffected by treatment. Accordingly, exposure of pregnant rats or rabbits to 50, 500, or 1000 mg/kg of PSF during the period of major organogenesis did not result in any biologically significant adverse or teratogenic effects in the dams or fetuses.

Subchronic inhalation toxicity of 1,1,1,3-tetrachloropropane in rats.

The purpose of this study was to evaluate the inhalation toxicity of 1,1,1,3-tetrachloropropane (TCP), an intermediate in the production of chlorinated silicone fluids. Male and female Sprague-Dawley rats were exposed 6 hr/day, 5 days/week, for 90 days to TCP at concentrations of 0, 25, 75, or 225 ppm (Phase I study) and to 0, 1, 5, or 10 ppm (Phase II study). Phase II of the study was conducted because a no-observed-effect level was not achieved in Phase I. No animals died during the study. Clinical signs of toxicity included oral, nasal, and/or ocular discharge. No statistically significant differences were observed in either body weights or food consumption between exposed and control animals. Clinical pathology did not indicate any treatment-related effects. Absolute and relative liver and kidney weights were increased in male and female rats exposed to 225 ppm TCP, and heart weights were increased in male rats exposed to 225 ppm TCP. The liver and heart weight changes were supported by the findings of microscopic lesions in these organs. These lesions consisted of multifocal/focal myofiber degeneration necrosis with adjacent chronic myocarditis in the heart and multifocal single-cell necrosis in the liver parenchyma. The liver lesions had essentially resolved at the end of a 28-day recovery period but the heart lesions were still present in male rats in the recovery group exposed to 225 ppm TCP. No treatment-related effects were observed in animals exposed to 1, 5, or 10 ppm TCP.(ABSTRACT TRUNCATED AT 250 WORDS)

Reproductive and developmental toxicity studies of silicone gel Q7-2159A in rats and rabbits.

Studies reported here assessed the potential adverse effects of silicone gel, Dow Corning Q7-2159A, on general reproduction and fetal development in male and female Charles River CD rats and New Zealand white rabbits. Two control and three treatment groups of 30 male and 30 female rats and 25 female rabbits per group were used in the one-generation reproduction and developmental toxicity studies, respectively. The silicone gel was implanted subcutaneously in two flank sites at dosage levels of 3, 10, and 30 ml/kg. The highest dose was selected on the basis of likely human body burden. Control groups received either sterile saline or carboxymethylcellulose solution in two flank implantation sites. The control and test articles were implanted in male and female rats 61 and 47 days, respectively, prior to mating (in the rat reproduction study) and approximately 42 days prior to insemination of female rabbits (in the rabbit developmental toxicity study). There were no treatment-related effects on F0 parental general conditions and reproductive performance, F1 neonatal viability, or growth in the rat reproduction study. No maternal nor developmental effects, including teratogenicity, were observed in rabbits in the groups implanted with Q7-2159A gel in the developmental toxicity study.

Reproductive and developmental toxicity studies of silicone elastomer Q7-2423/Q7-2551 in rats and rabbits.

The purpose of these studies was to assess the potential adverse effects of silicone breast implant envelope elastomer on general reproduction and fetal development in rats and rabbits. One control and one treatment group of 30 male and 30 female Charles River CD rats and 25 inseminated New Zealand white rabbits per group were used in the one-generation reproductive and developmental toxicity studies, respectively. Two 1.2-cm discs of silicone elastomer were subcutaneously implanted in one site in the left flank and one site in the right-flank of the treated group of rats, while four 2.5-cm discs were implanted in two sites in the left flank and two sites in the right flank of the treated group of rabbits. The size of the elastomer implants was chosen to approximate the expected body burden of women with breast implants. The control animals in both studies received subcutaneous implantation of either 1.2- or 2.5-cm discs of polyethylene of the same number in the same locations. The control and test articles were implanted in the male and female rats at 61 and 47 days, respectively, prior to mating (in the rat reproduction study) and approximately 42 days prior to insemination of female rabbits (in the rabbit developmental toxicity study). Subcutaneously implanted discs of silicone breast implant envelope elastomer did not induce maternal or developmental toxicity before or during pregnancy or during lactation, did not cause any adverse effects on the parents or neonates, and did not impair reproductive performance in the rat reproduction study. No maternal toxicity or adverse developmental effects, including teratogenicity, were observed in the treated groups in the rabbit developmental toxicity study.

Quaternary silsesquioxane: a developmental toxicity study in rats.

The developmental toxicity of an antimicrobial organosilicon quaternary ammonium chloride (Quaternary Silsesquioxane) was evaluated in rats. Groups of 25 pregnant CD rats were administered 100, 300, or 1000 mg/kg/day of test material by gavage as a single daily dose on Days 6 through 15 of gestation at a volume of 10 ml/kg. The control group received only corn oil as the vehicle. Cesarean examinations were performed on all females on Gestation Day 20 followed by evaluation of the fetuses for teratogenicity. Maternal effects included a slight but statistically significant increase in relative liver weights at the 1000 mg/kg/day dose level. Using these hepatic changes as an adverse effect, the maternal no observable adverse effect level for this study was identified at 300 mg/kg/day. The number of corpora lutea, implantation sites, viable fetuses, and early and late resorptions, the fetal body weights, the crown-rump length, and the gravid uterine and corrected body weights were not affected by the administration of Quat-Silsesquioxane. The occurrence of external and internal soft tissue malformations and variations and the incidences of skeletal malformations and variations in the treated groups were not significantly different from those in the control group. These results demonstrated that oral administration of Quat-Silsesquioxane as high as 1000 mg/kg/day did not produce teratogenicity or other indications of developmental toxicity in the rat conceptus.

Subchronic inhalation toxicity of tetramethoxysilane in rats.

Sprague-Dawley rats were exposed 6 hr/day, 5 days a week, for 28 days to tetramethoxysilane (TMOS) at concentrations of 0, 1, 5, and 10 ppm (Phase I study) and to 0, 15, 30, and 45 ppm (Phase II study). All of the rats exposed to 45 ppm TMOS died or were sacrificed in a moribund state during the 28-day study period. Statistically significant changes were observed in food consumption, body weights, and clinical chemistry parameters in the animals exposed to 30 ppm TMOS. Males exposed to 15 ppm TMOS showed a significant decrease in total protein. No effects were seen in rats exposed to 1, 5, and 10 ppm TMOS. Histopathological lesions related to TMOS exposure were observed in the respiratory tract tissues and eyes of rats exposed to 15, 30, and 45 ppm TMOS. The principal types of lesions observed were ulceration, inflammation, and necrosis of epithelium. At 45 ppm, changes at these sites were severe and present in all animals. Changes at 30 ppm, while occurring in all rats, were much less severe than those seen at 45 ppm. At 15 ppm, the changes were minimal and occurred only in three males and five females. The data of this study showed that TMOS has a steep dose-response curve with no observable effects at 10 ppm, very minimal effects at 15 ppm, moderate to severe effects at 30 ppm, and severe effects and lethality at 45 ppm.

Teratological evaluation of gamma-glycidoxypropyltrimethoxysilane in rats.

The embryotoxic and teratogenic potential of gamma- glycidoxypropyltrimethoxysilane ( GPTS ) was evaluated in rats. Pregnant Sprague-Dawley rats were administered 0, 50, 500, or 1,000 mg/kg/day of GPTS by gavage on days 6 through 15 of gestation. No treatment related signs of toxicity, behavioral alterations or mortalities were observed in any of the pregnant animals. There was no evidence of adverse effects in mean maternal body weight, liver weight or food consumption of the treated females. The number of implantation sites, number of live fetuses per litter, the mean litter size, the sex ratio, the fetal body weight or the crown-rump length were not affected by treatment. The incidence of resorptions among the total fetal population was not altered by the administration of GPTS to pregnant rats, indicating that the test material is not embryolethal in rats at the tested dose levels. Few scattered incidences of fetal alterations in the external, soft tissue or skeletal examinations were seen both among treated and untreated litters, however, no single alteration was observed in treated litters at an incidence which was significantly different from the control. In conclusion GPTS was not embryotoxic or teratogenic in rats at dose levels up to 1000 mg/kg/day.

Percutaneous absorption of an antimicrobial organosilicon quarternary ammonium chloride in rabbits.

The percutaneous absorption of an organosilicon quaternary ammonium chloride (14C)-3-(trimethoxysilyl)-propyldimethyloctadecyl ammonium chloride (14C-Si-QAC) was studied in rabbits. Aqueous solution of 14C-Si-QAC was either applied to the intact, clipped back of animals for 10 days or administered by a single intravenous dose. Urine and feces were collected at 24-h intervals and tissue concentration of radioactivity was determined at the end of the 10-day study period. Elimination of 14C-Si-QAC after parenteral administration was slow and occurred by both urine and feces (13.5% in urine and 20% in feces). No radioactivity was found in the urine of dermally treated animals. Tissue concentrations of 14C were highest in the liver, lung and kidneys after i.v. administration. None was detected in tissues of dermally treated animals. The results showed that the absorption of 14C-Si-QAC through the skin of the rabbit was essentially zero. The potential absorption hazard of the use of this antimicrobial agent in contact with the skin is therefore considered to be insignificant.

Subchronic oral toxicity study of gamma-glycidoxypropyltrimethoxysilane in rats.

The subchronic toxicity (28 days) of orally administered gamma-Glycidoxypropyltrimethoxysilane (GPTS) was studied in laboratory rats. The test material was administered daily for four weeks to groups of 10 male and 10 female Sprague-Dawley rats by gavage at dose levels of 0, 40, 400, and 1,000 mg/kg. Mortality, behavioral reactions, growth and food consumption were observed and measured along with hematology, blood biochemistry, absolute and relative organ weights. No overt signs of toxicity or behavioral abnormalities were observed in any of the test animals during the course of the study. There were no treatment related mortalities and no significant differences were observed in mean body weight, food consumption, absolute or relative organ weights of control and treated rats. Also, there were no meaningful differences in hematology, urinalysis or clinical blood chemistry values between control and treated animals. Gross and histopathologic examinations of organs or tissues from both control and GPTS treated animals did not reveal any treatment related changes. These results suggest that it is unlikely that serious injury would result from the ingestion of GPTS in amounts normally encountered incidental to its industrial use.

Subchronic dermal toxicity of trifluoropropylmethylcyclotrisiloxane in rabbits.

A 21-day subchronic dermal toxicity of trifluoropropylmethylcyclotrisiloxane (TFP) was conducted in New Zealand white rabbits. One control and three treatment groups of male and female animals were administered with the test material at levels of 0, 40, 200 and 400 mg/kg/day for three weeks. Mortality, behavioral reactions, growth and food consumption were observed and measured along with hematology, clinical blood chemistry, relative organ weight and pathology parameters. Five animals died at the highest dose level during the test period. Treatment with two higher dosages generally resulted in reduced rate of weight gain, lower food consumption, depressed serum alkaline phosphatase activity and increased activity of the serum enzymes. No significant adverse effects were observed at lower levels of 40 mg/kg. Gross pathologic examination revealed no treatment related causes of death and all organs and tissues were observed normal at the time of necropsy. There were no chemical related microscopic changes found in any of the test animals.

Subchronic dermal toxicity study of allyl methacrylate in rabbits.

A 28-day subchronic dermal toxicity of allyl methacrylate (AMA) was conducted in New Zealand white rabbits. Groups of six male and six female rabbits were treated with the test material at dose levels of 0, 25, 50 and 100 mg/kg/day for four weeks. One satellite group of male and female rabbits was also treated with 100 mg/kg/day of AMA. No overt signs of toxicity or abnormal behavior were seen among the rabbits during the treatment period. Two females from the 50 mg/kg/day group and two females at the highest dose level died during the course of the study. No mortalities and no significant adverse effects were observed in the low dose and control rabbits. Males treated with the highest dose level exhibited reduced weight gain and lower food consumption. The test material has no significant adverse effects on serum biochemistry, urine and hematological parameters or absolute and relative organ weights. No chemical related gross pathological alterations were observed in any of the organs or tissues examined at the time of necropsy except slight hemorrhage in the fascia of the skin of rabbits treated with 100 mg/kg/day of AMA. There were no significant chemical related microscopic changes found in any of the test rabbits. The animals of the satellite group appeared fully recovered following the 28-day dermal exposure to AMA. These results suggest that it is unlikely that AMA will present a significant health hazard from skin contact under normal conditions of industrial handling.

Skin sensitization potential of allyl methacrylate in guinea pigs.

The skin sensitization potential of allyl methacrylate (AMA) was studied in Hartley albino guinea pigs. Two groups of guinea pigs (10 per compound) were subjected to repeated insult patch tests either with AMA or with dinitrochlorobenzene (DNCB). All guinea pigs treated with DNCB (positive control) were sensitized. None of the guinea pigs treated with AMA exhibited any evidence of sensitization and no reactions attributable to AMA were elicited as a result of exposure during the insult phase of the patch test. Based on these results, it is concluded that allyl methacrylate is not likely to be a sensitizer and exposure to this material in industrial handling situations will not present an appreciable risk of human skin sensitization,

Pharmacokinetics and metabolic disposition of 14C-metronidazole-derived radioactivity in rat after intravenous and intravaginal administration.

Urinary metabolites and the pharmacokinetics of radioactivity derived from 14C-metronidazole (14C-MTZ) were determined after intravenous (iv) or intravaginal (ivg) administration of 10 mg/kg to adult rats. Following iv or ivg administration, the disappearance of 14C from blood followed the kinetics of a two-compartment open-system model. The blood half-lives of 14C during the beta-phase were 10.9 +/- 1.6 and 13.6 +/- 4.2 hr, after iv and ivg administration, respectively. After ivg application, the MTZ-derived radioactivity was detected in tail blood at 5 min, peaked at 1 hr, declined rapidly to 6 hr and more slowly thereafter. The vaginal absorption half-life of 14C-MTZ was 0.28 +/- 0.09 hr. About 12% of the administered dose remained in the vagina after 1 hr and 1.5% after 24 hr. At 24 hr, the tissue distribution and concentration of 14C were similar in iv and ivg dosed rats, the highest 14C concentration being present in the kidneys and lowest in the fat. The percentages of the dose excreted in 24 hr in the urine and feces were 58 and 15 after iv administration, compared to 37 and 40 after the ivg route, respectively. Unchanged 14C-MTZ and five of its metabolites were detected in the urine irrespective of the route of administration. The results show that metronidazole is rapidly absorbed through the vaginal mucosa of the rat and the metabolism and excretion of this chemotherapeutic agent are influenced by the route of administration.

The disposition of [14C]metronidazole in rats following vaginal and oral administration.

The absorption, tissue distribution and excretion of [17C]metronidazole (14C-MTZ) were compared during the first 4 h after administration of 10 mg kg-1 of 14C-MTZ either orally or intravaginally (i.v.g.) to rats. Peak 14C blood concentrations were reached at 1 h in both groups. Blood samples collected at 0.5, 3 and 4 h had a higher 14C concentration in orally dosed rats (P less than 0.05) than in i.v.g.-treated animals. About 3% of the i.v.g. applied dose remained in the vagina at 4 h. After 4 h, the plasma, liver, kidney, brain, lung and uterus concentrations of 14C were similar in both groups, whereas the blood, skeletal muscle and fat 14C values were significantly greater in the orally dosed rats. The total recoveries of 14C in the urine and faeces did not differ (ca 38% over 4 h) between the two groups. These results suggest that the kinetics of metronidazole are similar after the administration of equal amounts of this drug by either route.

Metronidazole: a comparative study on the intravaginal absorption, metabolism and disposition of a single product and commercial formulation.

The absorption, tissue distribution, metabolism and excretion of 14C-metronidazole (14C-MTZ) were compared during the first 24 hr upon the intravaginal (ivg) administration of 14C-MTZ, either as a single product (ivg-sp) or as a formulation in the form of a commercial cream (ivg-cp). Peak 14C levels in tail blood samples were reached at 1 and 2 hr in ivg-sp and ivg-cp treated rats, respectively. The rate of decline of blood 14C was faster in the ivg-sp treated rats as opposed to their ivg-cp treated counterparts. At the end of 24 hr, the highest 14C concentrations were observed in the kidneys and livers in both treatment groups. While the liver, kidney and lung concentrations of 14C were similar in both groups, the blood, plasma, brain, fat and skeletal muscle levels of 14C were significantly greater in the ivg-cp treated rats as compared with the ivg-sp treated animals. The combined excretion of radio-activity in the urine and feces of ivg-sp treated rats was significantly greater (77.7 +/- 3.0 vs. 58.0 +/- 2.0) than that of the ivg-cp treated animals. Irrespective of the product applied, about 1% of the applied dose remained in the vagina at the end of 24 hr. Unchanged 14C-MTZ and its five metabolites were detected from 0-12 and 12.24 hr urines of both groups. In comparison with the ivg-cp treated rats, the amount of unchanged 14C-MTZ was significantly greater in 0-12 hr urines of ivg-sp treated rats, whereas a reverse situation was observed during 12-24 hr period. The results of this study show that both products are almost completely absorbed through the vaginal mucosa of the rat; however, the kinetics of MTZ-derived radioactivity are different following the administration of equal amounts of each product.

Pharmacokinetics of triclosan in rat after intravenous and intravaginal administration.

The pharmacokinetics of triclosan was studied in sexually mature virgin Wistar rats. 14C-triclosan was injected either via the femoral vein, (iv, 5 mg/kg in polyethylene glycol-400) or into the vaginal orifice (ivg, 5 mg/kg in corn oil). Radioactivity was determined by liquid scintillation spectrophotometry. After iv administration, the dissapearance of 14C from the blood followed the kinetics of a two-compartment open-system model. The apparent volume of distribution was 42 percent of the body weight, which is more than the extracellular water, suggesting a rapid transfer of this antimicrobial agent from plasma to tissues. The blood half-life of 14C during the beta-phase was 8.8 +/- 0.6 hr and the blood clearance rate was 77.5 +/- 11.3 ml/kg/hr. After ivg administration of 14C-triclosan, the radioactivity was detected in tail blood at 15 min, peaked between 2 to 4 hr, and declined rapidly to 6 hr more slowly thereafter. About 26 percent of the administered dose remained in the vagina after 4 hr and 12 percent after 24 hr. Tissue concentrations of 14C were highest in the plasma, kidney, and liver after ivg application, but extremely low in the brain, fat, and skeletal muscle. The percentages of the dose excreted in 24 hr in the feces and urine were 18 and 9 after iv administration, compared to 26 and 14 after the ivg route, respectively. The results show that triclosan is rapidly absorbed through the vaginal mucosa of the rat.