p-Aminopropiophenone

149.19

149.19

200-742-7

79GF917W6U

404994|3187

2811

DTXSID7021738

Platelets from alcohol, water; needles from water|Yellow needles from water

2922399090

43.1

1.25 (est)

Propiophenone, 4'-amino- appears as yellow needles. (EPA, 1998)

1.1±0.1 g/cm3

140 °C

482 °C

138.7±20.4 °C

1.559

In water, 352 mg/L at 37 deg C

5.02X10-4 mm Hg at 25 deg C (est)

Oral-rat LD50: 177 mg/kg; Oral-Mouse LD50: 168 mg/kg

Flammable; generates toxic nitrogen oxide fumes when exposed to heat

Henry's Law constant = 4.60X10-9 atm-cu m/mol at 25 °C (est)

pKa = 2.64 (est)

Needles, yellowish cast, mp 198-199 °C. Freely soluble in water /p-Aminopropiophenone hydrochloride/|Hydroxyl radical reaction rate constant = 9.94X10-11 cu cm/molec-sec at 25 °C (est)

No rapid reaction with air. No rapid reaction with water.

Ketones

4'-AMINOPROPIOPHENONE is a ketone- and amine-substituted aromatic compound. Neutralizes acids in exothermic reactions to form salts plus water. May be incompatible with isocyanates, halogenated organics, peroxides, phenols (acidic), epoxides, anhydrides, and acid halides. Flammable gaseous hydrogen may be generated in combination with strong reducing agents, such as hydrides.

III

6.1(b)

2811

25

45-28A

T

Warehouse ventilated, low temperature and dry

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational harm/injury/toxicity or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal and plant life; and conformance with environmental and public health regulations.

Excerpt from ERG Guide 154 [Substances - Toxic and/or Corrosive (Non-Combustible)]: Non-combustible, substance itself does not burn but may decompose upon heating to produce corrosive and/or toxic fumes. Some are oxidizers and may ignite combustibles (wood, paper, oil, clothing, etc.). Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated. For electric vehicles or equipment, ERG Guide 147 (lithium ion batteries) or ERG Guide 138 (sodium batteries) should also be consulted. (ERG, 2016)

Excerpt from ERG Guide 154 [Substances - Toxic and/or Corrosive (Non-Combustible)]: SMALL FIRE: Dry chemical, CO2 or water spray. LARGE FIRE: Dry chemical, CO2, alcohol-resistant foam or water spray. Move containers from fire area if you can do it without risk. Dike fire-control water for later disposal; do not scatter the material. FIRE INVOLVING TANKS OR CAR/TRAILER LOADS: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. (ERG, 2016)

Excerpt from ERG Guide 154 [Substances - Toxic and/or Corrosive (Non-Combustible)]: As an immediate precautionary measure, isolate spill or leak area in all directions for at least 50 meters (150 feet) for liquids and at least 25 meters (75 feet) for solids. SPILL: Increase, in the downwind direction, as necessary, the isolation distance shown above. FIRE: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. (ERG, 2016)

Excerpt from ERG Guide 154 [Substances - Toxic and/or Corrosive (Non-Combustible)]: ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINERS. (ERG, 2016)

For emergency situations, wear a positive pressure, pressure-demand, full facepiece self-contained breathing apparatus (SCBA) or pressure- demand supplied air respirator with escape SCBA and a fully-encapsulating, chemical resistant suit. (EPA, 1998)

Releases of CERCLA hazardous substances are subject to the release reporting requirement of CERCLA section 103, codified at 40 CFR part 302, in addition to the requirements of 40 CFR part 355. 4-Aminopropiophenone is an extremely hazardous substance (EHS) subject to reporting requirements when stored in amounts in excess of its threshold planning quantity (TPQ) of 100 or 10,000 lbs. Extremely hazardous substances that are solids are subject to either of two threshold planning quantities ... The lower quantity applies only if the solid exists in powdered form and has a particle size less than 100 microns; or is handled in solution or in molten form; or meets the criteria for a National Fire Protection Association (NFPA) rating of 2, 3 or 4 for reactivity. If the solid does not meet any of these criteria, it is subject to the upper ... threshold planning quantity ... .

highly toxic

The bioactivation of the cyanide antidote methemoglobin former 4-aminopropiophenone (4-PAPP) was studied using rat and human microsomes. With rat liver and NADPH in single and two-compartment systems, dapsone and benzocaine were more potent methemoglobin generators compared with 4-PAPP. In the single compartment studies, the order of potency of inhibition of 4-PAPP-mediated methemoglobin formation was cimetidine (1.5 mM)>isoniazid (500 uM)/diethyldithiocarbamate (DDC, 1 mM)>erythromycin (500 uM). Human liver microsomal activation of 4-PAPP in the two-compartment system was partially inhibited by both DDC and cimetidine. These preliminary studies suggest that 4-PAPP may be metabolized by /cytochromes P450/ 2C11, 2E1 and 3A in the rat and /cytochromes P450/ 2C, 2E1 and probably 3A4 in man.|Nitrobenzene, aniline, p-aminotoluene (p-AT), p-aminoacetophenone (p-AAP) and p-aminopropiophenone (p-APP) have widely different activities as methemoglobin-forming agents in mice. As assessed by circulating levels after intra-peritoneal administration, p-AT was the least potent compound of the series, but nitrobenzene and aniline were also only weakly active even at lethal doses. Three hydroxylamine analogues from the above series were all about equipotent as methemoglobin forming agents in mice. Moreover, at a dose of 0.1 mole/kg each produced a transient methemoglobinemia that was remarkably similar to that resulting from p-APP. A methemoglobinemia with similar temporal characteristics was also produced by o-aminophenol, but this compound is about ten times less potent. p-Aminophenol was even weaker, being about as active as aniline. When aniline or nitrobenzene was given in combination with sodium nitrite, circulating methemoglobin levels were prolonged. Such a synergism was not seen when either was given in combination with p-APP. Methylene blue in vivo attenuated the methemoglobinemic response to both p-APP and nitrite. It was more effective, however, against the latter, as evaluated at doses that produced equivalent peak circulating levels. In its time pattern the effect of nitrite was similar in vivo (intact mouse) and in vitro (mouse red cell suspension). In contrast, methemoglobinemia produced by phenylhydroxylamine appears to persist longer in red cells than in the intact animal. Apparently, factors external to the red cell are important in terminating some kinds of induced methemoglobinemias.|Pretreatment with sodium nitrite or p-aminopropiophenone has been shown to protect armadillos, rabbits, and mice from death by parenteral sodium sulfide. The degree of protection correlated with anticipated levels of methemoglobinemia. Pretreatment of mice with nitrite or PAPP significantly prolonged their survival during continuous vapor exposure to any one of three concentrations of hydrogen sulfide, but the greatest protection occurred at the intermediate concentration. Under certain conditions propylene glycol also prolonged survival time, probably by a nonspecific action in depressing respirations. The mechanism of protection against sulfide by methemoglobinemia is discussed with reference to the formation of sulfmethemoglobin and its possible fate in vivo.

LD50 Rat oral 177 mg/kg (95% confidence interval: 119-262 mg/kg)|LD50 Mouse oral 233 mg/kg (95% confidence interval: 186-292 mg/kg)|LD50 Cat oral 5.6 mg/kg bw (in 0.05% Carbopol 914)|LD50 Guinea pig 1020 mg/kg bw

/BIRDS and MAMMALS/ Development of p-aminopropiophenone (PAPP) as a toxicant for pest predator management in New Zealand and Australia prompted investigation of its toxicity to potential nontarget species. Acute oral toxicity of PAPP in brushtail possums (Trichosurus vulpecula), dama wallabies (Macropus eugenii), and Mallards (Anas platyrhynchos) was estimated in pen trials, carried out between February 2000 and September 2001. The susceptibility of possums (LD50>or=500 mg/kg) and wallabies (LD50 89 mg/kg) to PAPP was low in comparison to noncarnivorous placental mammal species, but ducks (LD50 38 mg/kg) were more susceptible than other bird species. These results suggest that the nontarget hazard to possums and wallabies from PAPP bait applied for pest predator control would be low. However, future development of PAPP as a vertebrate pest control agent should include rigorous assessments of the hazard posed by bait formulations to bird species and provision for delivery techniques that could mitigate exposure of nontarget birds.

The comment is made that the frequency of polymorphism for MetHb reductase in caucasians is rare, and 15% in Inuit [Eskimos].|The frequency of glucose-6-phosphate dehydrogenase [deficiency] allele is up to 0.25% in general, but in subpopulations of tropical Africa, the Middle East and subtropical Asia, some areas of the Mediterranean and Papua New Guinea, frequencies as high as 5- 25% are found. ... Glucose-6-phosphate dehydrogenase deficiency is an X-chromosome linked recessive hereditary disease (which means significant phenotypic expression is more common in males, but heterozygous women can also develop haemolytic attacks). This is the most common human genetic defect, and occurs widely in people from Africa, Middle East and South Asia and people having genetic lineage to people from those areas. It is associated with some resistance to malaria. ...|... Genetic variants in cytochrome B5 (seen in people of Mediterranean or African origin) and hemoglobin (such as sickle cell disease) are more susceptible /to the effects of p-aminopropiophenone/.

4-Aminopropiophenone's production and use as an antidote(1) may result in its release to the environment through various waste streams(SRC). Its use as a vertebrate toxic agent in New Zealand(2) will result in its direct release to the environment(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 50(SRC), determined from a structure estimation method(2), indicates that 4-aminopropiophenone is expected to have very high mobility in soil(SRC). However, aromatic amines are expected to bind strongly to humus or organic matter in soils due to the high reactivity of the aromatic amino group(3,4), suggesting that mobility may be much lower in some soils(SRC). Volatilization of 4-aminopropiophenone from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 4.6X10-9 atm-cu m/mole(SRC), using a fragment constant estimation method(5). 4-Aminopropiophenone is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 5.0X10-4 mm Hg at 25 °C(SRC), determined from a fragment constant method(6). Biodegradation data were not available(SRC, 2011).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 50(SRC), determined from a structure estimation method(2), indicates that 4-aminopropiophenone 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 4.6X10-9 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of one(SRC), from an estimated log Kow of 1.25(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data were not available(SRC, 2011).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 4-aminopropiophenone, which has an estimated vapor pressure of 5.0X10-4 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 4-aminopropiophenone 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 1.3 hours(SRC), calculated from its rate constant of 9.9X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase 4-aminopropiophenone will be removed from the atmosphere by wet or dry deposition. 4-Aminopropiophenone absorbs light at wavelengths of 310.3 nm(4), and therefore may be susceptible to direct photolysis by sunlight(SRC).

The rate constant for the vapor-phase reaction of 4-aminopropiophenone with photochemically-produced hydroxyl radicals has been estimated as 9.9X10-11 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 1.3 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). 4-Aminopropiophenone is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(2). 4-Aminopropiophenone absorbs light at wavelengths of 310.3 nm(3), and therefore may be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of one was calculated in fish for 4-aminopropiophenone(SRC), using an estimated log Kow of 1.25(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).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of 4-aminopropiophenone can be estimated to be 50(SRC). According to a classification scheme(2), this estimated Koc value suggests that 4-aminopropiophenone is expected to have very high mobility in soil. However, aromatic amines are expected to bind strongly to humus or organic matter in soils due to the high reactivity of the aromatic amino group(3,4), suggesting that mobility may be much lower in some soils(SRC).

The Henry's Law constant for 4-aminopropiophenone is estimated as 4.6X10-9 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that 4-aminopropiophenone is expected to be essentially nonvolatile from water and moist soil surfaces(2). 4-Aminopropiophenone is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 5.0X10-4 mm Hg(SRC), determined from a fragment constant method(3).

Occupational exposure to 4-aminopropiophenone may occur through inhalation and dermal contact with this compound at workplaces where 4-aminopropiophenone is produced or used. Use data indicate that exposure to 4-aminopropiophenone will be limited to those administered this compound in drug products containing 4-aminopropiophenone, a cyanide antidote. (SRC)

/EXPERIMENTAL THERAPY:/ Controlled methemoglobin (MHb) formation is one strategy employed to counter cyanide (CN) toxicity. Currently available MHb formers present certain drawbacks and limitations. The purpose of this study was to characterize, in mice, the hematologic effects of the MHb-forming compound p-aminopropiophenone (PAPP), and two structurally-related p-aminophenones, p-aminoheptanoylphenone (PAHP) and p-aminooctanoylphenone (PAOP). Although these three p-aminophenones have been shown previously to be efficacious as pretreatments against CN, a more complete understanding of their hematologic effects is lacking. In addition, because the active form of PAPP has been shown to be its N-hydroxy metabolite, the N-hydroxy metabolites of PAPP, PAHP and PAOP were also tested. Using a hemoximeter, blood samples obtained -2 to +180 min relative to intramuscular (im) or intraperitoneal (ip) drug injections were evaluated. Sodium nitrite (NaNO2) and the appropriate solvents served as the positive and negative controls, respectively. Dose-, time-, route-, and compound-related effects were observed. MHb and sulfhemoglobin levels increased, whereas levels of those parameters related to oxygen-carrying capacity of the blood, such as, oxygen saturation and oxyhemoglobin decreased. In general, the effects of PAHP and PAOP were longer lasting than those of PAPP and NaNO2. Furthermore, PAPP and NaNO2 were equally effective with either route of administration. Conversely, PAHP and PAOP showed larger effects when administered ip versus im. The animals treated with N-hydroxy metabolites of the p-aminophenones also showed similar changes in the hematological parameters measured. N-hydroxy PAPP was shown to be the most rapidly acting MHb-forming compound examined in this series. It could achieve therapeutic concentrations of MHb within 2 min and thus may be considered as a treatment for CN intoxication...|/EXPERIMENTAL THERAPY:/ There is an interest and need for new compounds that protect tissues from radiation injury. In cancer therapy, the protection of normal tissue without protecting tumors is one way to increase the therapeutic gain. Thiol compounds are currently in clinical trials, but are limited to some extent by their human toxicities including hypotension, nausea, and emesis. Several new aminochalcones and aminobenzophenones were synthesized and tested for radioprotective activity in mice. All were less active than p-aminobenzophenone itself. Several acid hydrazides were synthesized and tested similarly, but none exhibited significant activity. The high radioprotective activity of 4-nitroaniline was confirmed, but other nitro amines were substantially less active. 4-Chloro-N-methylaniline is as active as 4-chloroaniline, but other chloro aromatics are devoid of significant activity. When compared with the phosphorothioate amyfostine (WR-2721) using the intestinal clonogenic cell survival assay, 1-(p-aminophenyl)-1-propanol, p-aminopropiophenone, its ethylene ketal, and a mixture of the two protected to a great extent, though slightly less than WR-2721. These results suggest that there is direct cellular radioprotection by these non-thiol compounds...|/EXPERIMENTAL THERAPY:/ ... Of twelve compounds that had been found to exhibit high radioprotective activity by ip injection, only two p-aminopropiophenone and its ethylene ketal retain that high activity (92-95 % survivors) when administered orally...|THERAPEUTIC CATEGORY: Antidote (cyanide)

Drugs used to protect against ionizing radiation. They are usually of interest for use in radiation therapy but have been considered for other purposes, e.g. military. (See all compounds classified as Radiation-Protective Agents.)

Sprague Dawley rats /were administered a single/ 5 mg PAPP/kg bw /dose/ by gavage. Rat excretion was rapid primarily in the urine, but 9% in feces, and a small proportion of a radio label 4-6% was found in expired air. [The authors claim this only applies in males, this conclusion is flawed. The estimate is based on radiolabel studies. The label was on the carbonyl atom for the male rats but on the benzene ring for the females. It is likely that the exhaled label was from metabolism to CO2, which would only be seen in the males in the study.]|The bioavailability of the PAPP from /a/ 0.4 mg/kg bw/day gavage dose was 32 +/- 10% (the bioavailability depended on the formulation, the range being 20 - 47%), and the time to the maximum methemoglobin concentration was 60 - 90 minutes. The peak methemoglobin was stated to lagged behind the peak plasma drug concentration by at least 60 minutes. This report proposes that PAPP is oxidized by cytochrome P450 (possibly in the lung) and then enters the blood where some of active metabolite oxidizes hemoglobin. This study demonstrates relatively high and rapid absorption via the oral route ... The short period time before the peak methemoglobin concentration (about 90 minutes for PAPP) indicates that the substance is readily metabolized and excreted, as would be expected from the structure of the molecule (with the possible exception of cats).|... The proportion of the PAPP dose excreted in urine is reduced with increasing dose.|Cynomologus monkeys /were administered/ 25 mg/kg bw (14)C-labeled to four monkeys for metabolism studies (by gavage). Excretion was rapid primarily in the urine, but slower in females than males.

Carworth farms, CF1 female mice /were administered p-aminopropiophenone at/ doses /of/ 10, 20, 30 mg PAPP/kg bw by intraperitoneal injection. Wet chemistry methods were used to analyze an active metabolite in the urine at different time periods. PAPP was excreted in urine both unchanged and as the acetyl derivative. The proportion of the PAPP dose excreted in urine reduced with increasing dose.|The N-hydroxy derivatives of p-ethylaniline, p-chloroaniline, p- and m-aminopropiophenone, 4-aminobiphenyl, and 2-aminofluorene were found in the urine after injection. Rabbits excrete 30 per cent of the p-aminopropiophenone and 20 per cent of the 4-aminobiphenyl as N-hydroxy derivative. The N-hydroxy derivatives of the other amines appear in the urine to a much smaller extent. Guinea pigs excrete a smaller proportion of the amines as N-hydroxy derivative than rabbits; 15 per cent of p-amino-propiophenone was found in the urine as N-hydroxy derivative. Dogs excrete only 1 per cent or less of the amines tested as N-hydroxy derivative. N-Hydroxy-p-amino-propiophenone is excreted to a large extent as a conjugate which is split in acid solution. The fraction of p-aminopropiophenone excreted as N-hydroxy derivative is the same over a wide range of doses. The relationship between the concentration of N-hydroxy derivative, and nitroso analogue, in the blood and urine of rabbits is quite different from that observed in dogs.|Sprague Dawley rats /were administered a single/ 5 mg PAPP/kg bw /dose/ by gavage. Rat urine contained three major components, unchanged PAPP (10%), N-acetyl-p-aminobenzoic acid (60%) and an unidentified polar compound which the authors concluded was the sulphate conjugate of N-acetyl-p-aminobenzoic acid (it could be the glucuronic acid conjugate). 4-N hydroxyl amino propiophenone (PHAPP) is generally believed to the proximate methaemoglobin generator, but this or degradation products of it were not found.|Four beagle dogs /were administered / 0.5 mg PAPP/kg bw ... for excretion studies. One mg/kg bw to four animals for metabolism studies. Excretion was rapid primarily in the urine. N-acetyl derivatives were not seen, the radioactivity was present in unchanged PAPP, 4-amino, 3-hydroxypropiophenone and the beta-hydroxylated derivative, both as sulphate conjugates.|The metabolic pathway in the monkeys was more complex than either the rat or dog. The same major pathway as rats occurs, but some of the p aminobenzoic acid appears as N-acetyl-p-aminophenol. PAPP is also metabolized to p-amino benzoic acid with is then conjugated with glycine to give para-aminohippuric acid. Analysis of methanol extract of monkey plasma showed 5% of the radioactivity was attributable to 4,4'-dipropionylazooxybenene (DAPB) /following 25 mg PAPP/kg bw (14)C-labeled)/, which could have resulted from PHAPP [the suggested methemoglobin forming metabolite].

Cyanide is a potent toxin that binds to cytochrome oxidase blocking electron transfer and the synthesis of adenosine triphosphate (ATP). Many antidotes to cyanide poisoning oxidize hemoglobin to methemoglobin (metHb), which serves as a scavenger of the cyanide anion. However, sufficiently high levels of metHb can be toxic because metHb cannot bind O2 until it is reduced. The purpose of the proposed study was twofold: (1) Characterize the time course of metHb formation for different doses of p-aminopropiophenone (PAPP), a drug that oxidizes hemoglobin and can be used as an antidote to cyanide intoxication; and (2) Determine whether the effort of an operant response affects the behavioral toxicity of metHb, since more effortful responses presumably are more energetically demanding. In Experiment I, the oral metHb kinetics of p-aminopropiophenone (PAPP) were studied; four doses of PAPP (1, 5, 10, and 20 mg/kg) or the vehicle, polyethylene glycol 200 (PEG200), were delivered via a gavage tube to separate groups of rats. In Experiment II, rats were trained to press a lever or run in an activity wheel at any time during a 12-hour light/dark cycle for their entire daily food intake; five presses or turns were required for the delivery of each food pellet. The same doses of PAPP were delivered /orally/ shortly before the onset of darkness, 2100 hr. Results from Exp I showed that PAPP induced a dose-dependent rapid increase and relatively slower exponential-like decline in metHb concentration. In Exp. II, the same doses of PAPP induced a dose-dependent reduction in hourly outputs of leverpresses and wheelturns however; wheelturns were reduced significantly more than leverpresses. When the best-fitting metHb curves from Experiment I were superimposed on the time scale for outputs of wheelturns and leverpresses, reduction of output was inversely related to the kinetics of metHb formation. These findings are consistent with the conclusion that PAPP-induced metHb formation reduced the output of wheelrunning more than leverpressing because the more energetically demanding response of wheelrunning was more affected by metHb induced hypoxemia. Furthermore, these data suggest that although certain longacting metHb formers might be useful prophylactics for warfighters, it will be critical to determine the energetic loads of required battlefield activities because even low (10%) therapeutic metHb levels might impair the performance of those activities.|p-Aminopropiophenone (PAPP) was found to produce a longer lasting methemoglobinemia than 4-dimethylaminophenol (DMAP) when given by gavage to dogs at doses producing peak methemoglobin levels of up to 26%. It was concluded that PAPP might be a more suitable substance for the pretreatment of cyanide poisoning than DMAP.|Twelve Schiff bases were prepared using salicylaldehyde, one with 5-chlorosalicylaldehyde, one with benzaldehyde, and a series of anilines substituted in the m- or p-positions. They were assayed for radioprotective activity in male, Swiss mice irradiated with a nearly lethal dose (950 cGy) of 6 mV photons produced by a linear accelerator, and were compared with the parent amines. Schiff base formation reduced toxicity of the parent amines; its effect on radioprotective activity was erratic, increasing activity in some cases, decreasing activity in others, and having no effect in ... others. Radioprotective activity appears to be unrelated to a number of molecular descriptors. The highest radioprotection (100%) was observed for mixtures of p-aminopropiophenone with its Schiff base, or with the Schiff base of 1-(p-aminophenyl)-1-propanol (95%).|Certain compounds that oxidize hemoglobin to methemoglobin (MHb) also protect against cyanide. Evidence presented here suggests that other mechanisms may be involved. Male Swiss ICR mice were pretreated intraperitoneally (ip) with various doses of primaquine phosphate (primaquine), WR6026 (6-methoxy-8-(6-diethylamino-hexylamino) lepidine dihydrochloride), WR238605 (8-[(4-amino-1-methylbutyl)amino]-2,6-dimethoxy-4-methyl-5-(3-trifluoromethylphenoxy) quinoline succinate), p-aminooctoyl-phenone (PAOP), or p-aminopropiophenone (PAPP). The compounds were administered 15 or 60 min before an intramuscular (im) challenge with a 2xLD50 dose (5.0-5.6 mg/kg) of sodium cyanide (NaCN). Twenty-four hr /later/ mortality was assessed and survivors were tested for motor incapacitation. Primaquine, PAPP and PAOP increased survival compared to untreated controls, while the other MHb formers were not effective (P < 0.05). PAOP is believed to form sufficient MHb only after 3 to 4 hr after administration; however it was found to be effective when administered 15 min before NaCN challenge in this study. This suggests that MHb formation may not be the only factor responsible for PAOP's anti-cyanide efficacy.|Benzocaine induces methemoglobin (MHb) in several species, whereas lidocaine may increase MHb in cats and human. Elevated MHb (>20%) in sheep after benzocaine exposure was recently recognized. MHb decreases blood oxygen-carrying capacity which can complicate interpretation of experimental data. Sheep are used in research which requires tracheal intubation and blood gas analysis. Since benzocaine and lidocaine are used to provide local anesthesia prior to intubation, we compared MHb production by sheep after exposure to these drugs. A dose-response relationship between benzocaine and MHb was investigated. Eight crossbred Dorset ewes were dosed intranasally with benzocaine for 2 sec or with 40 mg of lidocaine in a randomized crossover design. Sheep with elevated MHb after the 2-sec benzocaine dose were later dosed with benzocaine intranasally for 10 sec. MHb levels were measured periodically on a CO-Oximeter. A quantitative MHb response to an indirect MHb former, p-aminopropiophenone (PAPP), by each sheep was determined 15 min after PAPP (0.6 mg/kg iv). MHb levels remained at baseline (1-2%) after lidocaine exposure in all sheep, as well as in four sheep (nonresponders) after the 2-sec benzocaine dose. Four sheep (responders) demonstrated 16.5-26.4% MHb after the 2-sec benzocaine dose. The responders formed 38.2-50.5% MHb after the 10-sec benzocaine dose. All responders developed high MHb after PAPP, while nonresponders developed slightly elevated MHb after PAPP. An N-hydroxy metabolite of benzocaine is the likly active MHb-forming substance. Benzocaine should be replaced by lidocaine when local anesthesia of the nasal or oropharyngeal region in sheep is required.

Excerpt from ERG Guide 154 [Substances - Toxic and/or Corrosive (Non-Combustible)]: TOXIC; inhalation, ingestion or skin contact with material may cause severe injury or death. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. (ERG, 2016)

Warning: Propiophenone, 4-amino- induces methemoglobinemia. Treatment is most effective if initiated within 30 minutes. Ingestion of large doses can cause cyanosis (bluish discoloration of the skin and mucous membranes). Note: Methemoglobin levels will be artificially low if blood is not analyzed rapidly (i.e., within a few hours). Signs and Symptoms of Propiophenone, 4-Amino- Exposure: Signs and symptoms of acute exposure to propiophenone, 4-amino- may include cardiac arrhythmias and hypotension in severe cases, dyspnea (difficult or labored breathing), tachypnea (shallow, rapid breathing), headache, dizziness, syncope (fainting), lethargy progressing to convulsions, and coma. Gastrointestinal symptoms may include nausea and vomiting. Hematological symptoms may include methemoglobinemia and possible later development of hemolytic anemia. Emergency Life-Support Procedures: Acute exposure to propiophenone, 4-amino- may require decontamination and life support for the victims. Emergency personnel should wear protective clothing appropriate to the type and degree of contamination. Air-purifying or supplied-air respiratory equipment should also be worn, as necessary. Rescue vehicles should carry supplies such as plastic sheeting and disposable plastic bags to assist in preventing spread of contamination. Inhalation Exposure: 1. Move victims to fresh air. Emergency personnel should avoid self-exposure to propiophenone, 4-amino-. 2. Evaluate vital signs including pulse and respiratory rate, and note any trauma. If no pulse is detected, provide CPR. If not breathing, provide artificial respiration. If breathing is labored, administer oxygen or other respiratory support. 3. Obtain authorization and/or further instructions from the local hospital for performance of other invasive procedures. 4. Rush to a health care facility. Dermal/Eye Exposure: 1. Remove victims from exposure. Emergency personnel should avoid self-exposure to propiophenone, 4-amino-. 2. Evaluate vital signs including pulse and respiratory rate, and note any trauma. If no pulse is detected, provide CPR. If not breathing, provide artificial respiration. If breathing is labored, administer oxygen or other respiratory support. 3. Remove contaminated clothing as soon as possible. 4. If eye exposure has occurred, eyes must be flushed with lukewarm water for at least 15 minutes. 5. Wash exposed skin areas three times with soap and water. 6. Obtain authorization and/or further instructions from the local hospital for performance of other invasive procedures. 7. Rush to a health care facility. Ingestion Exposure: 1. Evaluate vital signs including pulse and respiratory rate, and note any trauma. If no pulse is detected, provide CPR. If not breathing, provide artificial respiration. If breathing is labored, administer oxygen or other respiratory support. 2. Obtain authorization and/or further instructions from the local hospital for performance of other invasive procedures. 3. Vomiting may be induced with syrup of Ipecac. If elapsed time since ingestion of propiophenone, 4-amino- is unknown or suspected to be greater than 30 minutes, do not induce vomiting and proceed to Step 4. Ipecac should not be administered to children under 6 months of age.Warning: Ingestion of propiophenone, 4-amino- may result in sudden onset of seizures or loss of consciousness. Syrup of Ipecac should be administered only if victims are alert, have an active gag-reflex, and show no signs of impending seizure or coma. If ANY uncertainty exists, proceed to Step 4.The following dosages of Ipecac are recommended: children up to 1 year old, 10 mL (1/3 oz); children 1 to 12 years old, 15 mL (1/2 oz); adults, 30 mL (1 oz). Ambulate (walk) the victims and give large quantities of water. If vomiting has not occurred after 15 minutes, Ipecac may be readministered. Continue to ambulate and give water to the victims. If vomiting has not occurred within 15 minutes after second administration of Ipecac, administer activated charcoal. 4. Activated charcoal may be administered if victims are conscious and alert. Use 15 to 30 g (1/2 to 1 oz) for children, 50 to 100 g (1-3/4 to 3-1/2 oz) for adults, with 125 to 250 mL (1/2 to 1 cup) of water. 5. Promote excretion by administering a saline cathartic or sorbitol to conscious and alert victims. Children require 15 to 30 g (1/2 to 1 oz) of cathartic; 50 to 100 g (1-3/4 to 3-1/2 oz) is recommended for adults. 6. Rush to a health care facility. (EPA, 1998)

/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/

/HUMAN EXPOSURE STUDIES/ This study used human volunteers from a factory site to investigate the methemoglobin (MetHb) response in humans. There were 51 individuals (assumed to be male, but this is not stated), aged between 23- 52 years of age. There exposures were to 100 mg (13 cases), 80 mg (37 cases) or 50 mg (1 case) PAPP. The study showed that it takes 15- 30 minutes for MetHb to develop, with the peak level being reached 1- 2 hours after consumption. In most individual receiving 80 or 100 mg the MetHb level was higher than 5% for at least 4 hours. The group data summaries were: 100 mg group: distribution of maximum level was 22 +/-14% (range 2- 48%); 80 mg group: distribution of maximum level was 13.1 +/-9% (range 0- 43%). [The one individual consuming 50 mg had 7% MetHb.] Effect of body weight: Due to the lack of adjustment of dose based on body weight, the MetHb response varied depending on body weight. For individual receiving 100 mg with MetHb concentrations >20% the average body weight was 63kg (average dose (1.28 mg/kg bw), while for those with 20%, the average body weight was 78 (1.59 mg/kg bw). For the individuals receiving 80 mg, the equivalent data are for MetHb concentrations >10% the average body weight was 71kg (average dose (1.13 mg/kg bw), while for those with 10%, the average body weight was 76 (1.05 mg/kg bw). Effect of food consumption: The study also appeared to demonstrate (based on different data) involving individuals who had consumed PAPP a long or short time after a meal that the MetHb level tends to be higher if it is a long time since a meal had been consumed, which was believed to be due to stomach acidity, but it may also related to dissolution of PAPP in lipid. Variability: The study also demonstrated that a small number of individuals are relatively resistant to the effects of MetHb generating substances. The report indicates 2-3 individuals in their group of 51 [but the generalizability of this to the human population needs caution, as the study is presumed to be of adult, male Caucasians only]. Questionnaires did not identify any subjective discomfort associated with the exposure to PAPP, even in individuals who had MetHb levels of 30- 40% and who were demonstrating clear signs of methemoglobinemia (blue lips). No changes in the ventilation rates or blood pressure were seen in comparison to pre-treatment values. Electrocardiograms for 20 of the individuals were carried out. There were no changes in 18 individuals, but two individuals, both of whom received the 80 mg dose [aged 25 and 37, weighing 67kg and 100 kg respectively] were found to have slight changes that were reported as minimal. The MetHb levels were respectively in these individuals were 24% and 4.5%.

4-aminopropiophenone

PAPP Paste A is a paste containing 410 g/kg para-aminopropiophenone (PAPP). PAPP Paste B is a paste containing 15 g/kg PAPP. PAPP Ready-to-use Bait is minced meat ball of 5 to 10 g containing equivalent to 3 - 10 g/kg PAPP.

1-Propanone, 1-(4-aminophenyl)-: ACTIVE