Tempol

Carrageenan causes enhanced formation of reactive oxygen species, which contribute to the pathophysiology of inflammation. We have investigated the effects of tempol, a membrane-permeable radical scavenger, in rats subjected to carrageenan-induced pleurisy. Treatment of rats with tempol (10, 30, or 100 mg/kg 15 min prior to carrageenan) attenuated the pleural exudation and the migration of polymorphonuclear cells caused by carrageenan dose dependently. Tempol also attenuated the lung injury (histology) as well as the increase in the tissue levels of myeloperoxidase and malondialdehyde caused by carrageenan in the lung. However, tempol did not inhibit the activity of inducible nitric oxide synthase in the lungs. Immunohistochemical analysis for nitrotyrosine revealed positive staining in lungs from carrageenan-treated rats. Lung tissue sections from carrageenan-treated rats also showed positive staining for poly-(ADP-ribose) synthetase (PARS). The degree of staining for nitrotyrosine and PARS was markedly reduced in tissue sections obtained from carrageenan-treated rats, which had received tempol (100 mg/kg). Furthermore, treatment of rats with tempol significantly reduced (i) the formation of peroxynitrite, (ii) the DNA damage, (iii) the impairment in mitochondrial respiration, and (iv) the fall in the cellular level of NAD(+) observed in macrophages harvested from the pleural cavity of rats treated with carrageenan. Tempol also attenuated the cell injury caused by hydrogen peroxide (1 mM) in cultured human endothelial cells. This study provides the first evidence that tempol, a small molecule which permeates biological membranes and scavenges ROS, attenuates the degree of inflammation and tissue damage associated with carageenan-induced pleurisy in the rat...

Rats develop acute pancreatitis when infused iv for 3 hr with cerulein (10ug/kg/hr). Autopsies of the pancreas seen by light microscope show interstitial edema, acinar cells vacuolization, and leukocyte margination in pancreatic capillaries; under electron microscope, severe damage concerning mitochondrial and zymogen granules structures are apparent. Particularly, swelling of the mitochondria and disruption of mitochondrial cristae was observed as well as formation of large vacuoles arising from zymogen granules and liposome fusion. A significant increase of lipid hydroperoxide level in the pancreatic tissue was observed. The purpose of this study was to evaluate the effect of 4-hydroxy-TEMPO--a low-mol-wt superoxide dismutase mimic--in a rat cerulein model of acute pancreatitis, with the expectation that free radical mediated hydroperoxide formation and tissue damage may be reduced significantly. Twenty-one male Wistar rats were divided into three groups: Group 1 (n = 5) served as a control and was infused iv for 3 hr with physiologic saline; Group 2 (n = 8) was infused i.v. for 3 hr with cerulein 10 micrograms/kg/hr; and Group 3 (n = 8) infused i.v. both with cerulein and 4-hydroxy-TEMPO 22.6 mg/kg/hr. Pancreatic tissue damage was quantified by measuring lipid hydroperoxide (LOOH) level, the weight of the organ, and by light and electron microscopic examination. 4-hydroxy-TEMPO penetration across cellular membrane barriers was quantified by ESR spectrometric measurements of 4-hydroxy-TEMPO concentration in pancreatic tissue samples and pancreatic juice as well. Administering 4-hydroxy-TEMPO to rats resulted in preventing both lipid hydroperoxide formation and severe morphological damage. 4-hydroxy-TEMPO crossed cellular membrane barriers and was excreted to pancreatic juice. Infusion of 4-hydroxy-TEMPO appears to prevent pancreatic injury caused by free radicals in experimental cerulein pancreatitis.

Hemorrhagic shock (HS) is associated with the generation of reactive oxygen species, which may contribute to delayed multiple organ system failure and death. Previous studies have shown that the antioxidant Tempol improved physiologic variables, although not necessarily outcome, in septic shock and HS. We hypothesized that the combination of free Tempol with polynitroxylated albumin (PNA)-bound Tempol (which prolongs half-life and decreases toxicity) improves outcome after HS in rats. In study 1, HS was induced by blood withdrawal of 3 mL/100 g over 15 minutes. Mean arterial pressure was maintained at 40 mm Hg with either infusion of normal saline or withdrawal of blood from 20 to 90 minutes. Resuscitation (90-270 minutes) was with infusion of shed blood. Observation was to 72 hours. At HS 45 min, albumin (ALB) (n = 10) or PNA + Tempol (n = 10) was infused slowly (1 mL/100 g/h) until 120 minutes. Study 2 was the same as study 1 (n = 6 per group), but terminated at 150 minutes. Study 3 was the same as study 1, but started with ALB or PNA + Tempol (n = 7 per group) at 20 minutes. The primary outcome variable in studies 1 and 3 was survival, whereas the primary outcome variables in study 2 were antioxidant reserve (ability of the serum or tissue homogenate to scavenge peroxyl radicals produced by 2,2'-azobis [2-aminodipropane]-dihydrochloride) in serum and small intestine, and low-molecular-weight thiols in tissues (liver, small intestine, and kidney). In study 1, 72-hour survival was 1 of 10 (ALB group) versus 2 of 10 (PNA + Tempol group). At 90 minutes, pH was lower in the ALB group versus the PNA + Tempol group (p = 0.02) and remained low. Arterial lactate increased to 8.9 +/- 3.2 (mean +/- SD) versus 6.5 +/- 1.8 mmol/L (p = 0.04) and base excess was -9.6 +/- 4.3 versus -5.2 +/- 3.2 mmol/L (p = 0.01) (ALB vs. PNA + Tempol groups, respectively). In study 2, antioxidant reserve in serum was lower in the ALB group versus the PNA + Tempol group (p = 0.002). There were no differences between groups in antioxidant reserve in the small intestine or low-molecular-weight thiols in liver, kidney, and small intestine. In study 3, 72-hour survival was zero of seven (ALB group) versus five of seven (PNA + Tempol group) (p = 0.02). Heart rate and systolic blood pressure during late HS were higher in the ALB group in studies 1 and 3 (p < 0.05). When infused early in HS, PNA + Tempol can increase survival. When given late, it significantly improves acid-base and serum antioxidant status, without an effect on survival...

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 40(SRC), determined from a structure estimation method(2), indicates that 1-piperidinyl, 4-hydroxy-2,2,6,6-tetramethyl- is expected to have very high mobility in soil(SRC). Volatilization of 1-piperidinyl, 4-hydroxy-2,2,6,6-tetramethyl- from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 3.0X10-15 atm-cu m/mole(SRC), using a fragment constant estimation method(3). 1-Piperidinyl, 4-hydroxy-2,2,6,6-tetramethyl- is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.0X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(4). Biodegradation data in soil were not available(SRC, 2012).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 40(SRC), determined from a structure estimation method(2), indicates that 1-piperidinyl, 4-hydroxy-2,2,6,6-tetramethyl- is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 3.0X10-15 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 3(SRC), from an estimated log Kow of 0.55(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2012).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 1-piperidinyl, 4-hydroxy-2,2,6,6-tetramethyl-, which has an estimated vapor pressure of 1.0X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase 1-piperidinyl, 4-hydroxy-2,2,6,6-tetramethyl- is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 9 hours(SRC), calculated from its rate constant of 1.4X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase 1-piperidinyl, 4-hydroxy-2,2,6,6-tetramethyl- may be removed from the air by wet or dry deposition(SRC). 1-Piperidinyl, 4-hydroxy-2,2,6,6-tetramethyl- absorbs at wavelengths >290 nm(4), and therefore may be susceptible to direct photolysis by sunlight(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of 1-piperidinyl, 4-hydroxy-2,2,6,6-tetramethyl- can be estimated to be 40(SRC). According to a classification scheme(2), this estimated Koc value suggests that 1-piperidinyl, 4-hydroxy-2,2,6,6-tetramethyl- is expected to have very high mobility in soil.

An estimated BCF of 3 was calculated in fish for 1-piperidinyl, 4-hydroxy-2,2,6,6-tetramethyl-(SRC), using an estimated/ log Kow of 0.55(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The Henry's Law constant for 1-piperidinyl, 4-hydroxy-2,2,6,6-tetramethyl- is estimated as 3.0X10-15 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that 1-piperidinyl, 4-hydroxy-2,2,6,6-tetramethyl- is expected to be essentially nonvolatile from water and moist soil surfaces(2). 1-Piperidinyl, 4-hydroxy-2,2,6,6-tetramethyl- is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.0X10-7 mm Hg(SRC), determined from a fragment constant method(3).

/LABORATORY ANIMALS: Acute Exposure/ Reactive oxygen species play critical roles in a number of physiologic and pathologic processes. Nitroxides are stable free radical compounds that possess superoxide dismutase (SOD) mimetic activity and have been shown to protect against the toxicity of reactive oxygen species in vitro and in vivo. Tempol, a cell-permeable hydrophilic nitroxide, protects against oxidative stress and also is an in vitro and in vivo radioprotector. In the course of evaluating the pharmacology and toxicity of the nitroxides, Tempol and another nitroxide, 3-carbamoyl-PROXYL (3-CP), were administered intravenously in various concentrations to miniature swine. Tempol caused dose-related hypotension accompanied by reflex tachycardia and increased skin temperature. Invasive hemodynamic monitoring with Swan Ganz catheterization (SGC) confirmed the potent vasodilative effect of Tempol. However, 3-CP had no effect on porcine blood pressure. The hemodynamic effects of Tempol and 3-CP are discussed in the context of differential catalytic rate constants for superoxide disumation that may impact systemic nitric oxide (NO) levels and lead to vasodilation. These findings are consistent with a role for the superoxide ion in the modulation of blood pressure and have potential implications for the systemic use of nitroxides.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Nitroxides are stable free radical compounds that protect against the toxicity of reactive oxygen species in vitro and in vivo. Tempol is a cell-permeable hydrophilic nitroxide and has been shown to be an in vitro and in vivo radioprotector. The limitations of Tempol as a systemic radioprotector are that it causes substantial reductions in arterial blood pressure when administered intravenously and is associated with seizure activity. Furthermore, Tempol is rapidly reduced to its hydroxylamine form, Tempol-H, which limits the period of time the active form of the nitroxide is available for radioprotection. Based on initial pharmacological and blood pressure experiments performed in mice, we hypothesized that the systemic administration of Tempol-H in vivo would lead to an equilibration between Tempol and Tempol-H that would limit the toxicity of the nitroxide and provide in vivo radioprotection. Tempol-H was administered in increasing doses via an intraperitoneal route to C3H mice. The maximally tolerated dose was found to be 325 mg/kg. The whole-blood pharmacology of Tempol-H was investigated with electron paramagnetic resonance spectroscopy. These studies demonstrated the appearance of Tempol in whole blood immediately after intraperitoneal injection, suggesting that rapid oxidation of Tempol-H to Tempol takes place in vivo. Although the peak concentration of Tempol in whole blood after administration of Tempol-H did not reach the same levels as those observed when Tempol is administered, the whole-blood levels of Tempol were similar by 10 min after injection. Tempol-H provided protection against the lethality of whole-body radiation in C3H mice at 30 days with a dose modification factor of 1.3, which is similar to the results obtained with Tempol. Hemodynamic measurements in C3H mice after intravenous injection showed that Tempol-H produced little effect on blood pressure or pulse compared with Tempol. Tempol-H is a systemic in vivo radioprotector of C3H mice and is associated with less hemodynamic toxicity than Tempol. /Tempol-H/

The rate constant for the vapor-phase reaction of 1-piperidinyl, 4-hydroxy-2,2,6,6-tetramethyl- with photochemically-produced hydroxyl radicals has been estimated as 1.4X10-11 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 9 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). 1-Piperidinyl, 4-hydroxy-2,2,6,6-tetramethyl- is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(2). 1-Piperidinyl, 4-hydroxy-2,2,6,6-tetramethyl- absorbs light at wavelengths >290 nm(3), and therefore may be susceptible to direct photolysis by sunlight(SRC).

According to the 2006 TSCA Inventory Update Reporting data, the number of persons reasonably likely to be exposed in the industrial manufacturing, processing, and use of 1-piperidinyloxy, 4-hydroxy-2,2,6,6-tetramethyl is 100 to 999; the data may be greatly underestimated(1).

Occupational exposure to 1-piperidinyl, 4-hydroxy-2,2,6,6-tetramethyl- may occur through inhalation and dermal contact with this compound at workplaces where 1-piperidinyl, 4-hydroxy-2,2,6,6-tetramethyl- is produced or used. (SRC)

1-Piperidinyl, 4-hydroxy-2,2,6,6-tetramethyl-'s production and use as a research chemical may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 1.0X10-7 mm Hg at 25 °C indicates 1-piperidinyl, 4-hydroxy-2,2,6,6-tetramethyl- will exist in both the vapor and particulate phases in the atmosphere. Vapor-phase 1-piperidinyl, 4-hydroxy-2,2,6,6-tetramethyl- will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 9 hours. Particulate-phase 1-piperidinyl, 4-hydroxy-2,2,6,6-tetramethyl- will be removed from the atmosphere by wet or dry deposition. 1-Piperidinyl, 4-hydroxy-2,2,6,6-tetramethyl- absorbs light at wavelengths >290 nm, and therefore may be susceptible to direct photolysis by sunlight. If released to soil, 1-piperidinyl, 4-hydroxy-2,2,6,6-tetramethyl- is expected to have very high mobility based upon an estimated Koc of 40. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 3.0X10-15 atm-cu m/mole. Biodegradation data in soil or water were not available. If released into water, 1-piperidinyl, 4-hydroxy-2,2,6,6-tetramethyl- is not expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. An estimated BCF of 3 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions (pH 5 to 9). Occupational exposure to 1-piperidinyl, 4-hydroxy-2,2,6,6-tetramethyl- may occur through inhalation and dermal contact with this compound at workplaces where 1-piperidinyl, 4-hydroxy-2,2,6,6-tetramethyl- is produced or used. (SRC)

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

A paramagnetic radical used in nuclear magnetic resonance (NMR) as a spin label; [ChemIDplus] Also used as a catalyst, antioxidant, and polymerization inhibitor; [Merck Index]

Spin label for EPR /electron paramagnetic resonance/ studies; phase transfer dehydration catalyst; antioxidant; inhibitor of olefin-free radical polymerization.

Tempol, a water-soluble piperidine nitroxide derivative having nonspecific radical-scavenging and superoxide dismutase (SOD) activity, protects cultured aerobic, but not hypoxic, cells against radiation-induced killing.

2023: 550,000 - <700,000 lb

Production volumes for non-confidential chemicals reported under the Inventory Update Rule. [Table#7962]

Production volume for non-confidential chemicals reported under the 2006 Inventory Update Rule. Chemical: 1-Piperidinyloxy, 4-hydroxy-2,2,6,6-tetramethyl-. Aggregated National Production Volume: 1 to < 10 million pounds.

Plastics Product Manufacturing

1-Piperidinyloxy, 4-hydroxy-2,2,6,6-tetramethyl-: ACTIVE