Mipafox

Biological Exposure Indices (BEI) [ACGIH] - Acetylcholinesterase activity in red blood cells = 70% of individual's baseline; Butylcholinesterase activity in serum or plasma = 60% of individual's baseline; Sample at end of shift; [TLVs and BEIs]

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure 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, aquatic, and plant life; and conformance with environmental and public health regulations.

The effects of aldicarb and verapamil on mipafox (371868) induced inhibition of neuropathy-target-esterase (NTE) activity in human neuroblastoma cells were examined. Differentiated SY-5Y (SY5Y) cells, a cell line derived from SK-N-SH-human neuroblastoma cells, were incubated with 0 or 5x10(-5) molar (M) mipafox in the presence or absence of 5x10(-3)M aldicarb or 1x10(-7)M verapamil for 2 to 10 minutes. The cultures were assayed for NTE activity. The ability of 25 millimolar isonitroacetophenone (INAP) to reactivate NTE activity was evaluated 2, 5, or 10 minutes after mipafox exposure. A similar experiment was performed in chicken brain homogenates. Mipafox caused a similar time dependent decrease of NTE activity in SY5Y cells and chicken brain homogenates. INAP was capable of reactivating NTE activity; however, the degree of reactivation decreased with increasing time between mipafox and INAP treatment. Aldicarb and verapamil countered the inhibitory effect of mipafox in both SY5Y cells and the brain homogenates. The authors conclude that NTE activity in SY5Y cells and chicken brain homogenates, the accepted model for organophosphate induced delayed neuropathy (OPIDN), is inhibited to a similar extent by mipafox. Aldicarb and verapamil exert inhibitory effects on the mipafox induced suppression of NTE activity in both preparations.

The toxic effects of phenylmethylsulfonyl-fluoride (329986) (PMSF) and Mipafox (371868), administered either singly or combined, were studied in 60 day old male Long-Evans-rats. Animals were treated with: 250 milligrams per kilogram (mg/kg) PMSF; 15mg/kg Mipafax; 250mg/kg PMSF followed 4 hours later by 15mg/kg Mipafax; 15mg/kg Mipafox followed 4 hours later by 250mg/kg PMSF; or 250mg/kg PMSF followed 14 days later by 15mg/kg Mipafax. Animals receiving single doses of either compound were sacrificed 1, 4, 24, 48, or 72 hours after administration and others were sacrificed 14 to 21 days postexposure. Assays were conducted to determine evidence of neuropathy, target enzyme, and damage to cervical cord. Animals receiving PMSF only were incapacitated for 48 hours and then resumed normal activity; no mortality occurred. Mipafox only animals experienced mild tremors and diarrhea; no mortality occurred in this group either. Animals receiving Mipafox 4 hours after PMSF had a 50 percent mortality rate and remained immobile for 48 hours after treatment. Animals receiving PMSF 4 hours after Mipafox had tremors which were eliminated after PMSF treatment which immobilized them for 48 hours; a 25 percent mortality rate occurred. There were no deaths among animals receiving Mipafox 14 days after PMSF, although the animals were similarly incapacitated.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 8.8(SRC), determined from a water solubility of 80,000 mg/L(2) and a regression-derived equation(3), indicates that mipafox is expected to have very high mobility in soil(SRC). Volatilization of mipafox from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant for mipafox of 3.0X10-9 atm-cu m/mole(SRC) derived from its vapor pressure, 0.001 mm Hg(4), and water solubility(2). Mipafox is not expected to volatilize from dry soil surfaces(SRC) based upon its vapor pressure(4). Biodegradation data were not available(SRC, 2005).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 8.8(SRC), determined from a water solubility of 80,000mg/L(2) and a regression-derived equation(3), indicates that mipafox 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 for mipafox of 3.0X10-9 atm-cu m/mole(SRC) derived from its vapor pressure, 0.001 mm Hg(4), and water solubility(2). According to a classification scheme(6), an estimated BCF of 1(SRC), determined from its water solubility(5) and a regression-derived equation(3), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Mipafox is reported to hydrolyze slowly under environmental conditions; a half life of 200 days was observed at pH 6(4). Biodegradation data were not available(SRC, 2005).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), mipafox, which has a vapor pressure of 0.001 mm Hg at 25 °C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase mipafox 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 4.2 hrs(SRC), calculated from its rate constant of 9.2X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Mipafox does not contain chromophores that absorb at wavelengths >290 nm and therefore would not be expected to be susceptible to direct photolysis by sunlight(SRC).

The Koc of mipafox is estimated as 8.8(SRC) using a water solubility of 80,000 mg/L(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that mipafox is expected to have very high mobility in soil.

/HUMAN EXPOSURE STUDIES/ ...Acetylcholinesterase inhibitor, like parathion. After acute phases of poisoning, degenerative lesions may become apparent in central and peripheral nervous systems.

/SIGNS AND SYMPTOMS/ ...Some cholinesterase-inhibiting organophosphorus compounds can produce permanent paralysis due to /PRC: secondary/ demyelinating process of spinal cord... Demyelination in man has been attributed only to mipafox, agent not used in United States.

/SIGNS AND SYMPTOMS/ See Parathion. Symptomatology: 1. Nausea...vomiting, abdominal cramps, diarrhea, excessive salivation... 2. Headache, giddiness, vertigo and weakness. 3. Rhinorrhea and sensation of tightness in chest are common in inhalation exposure. 4. Blurring or dimness of vision, miosis... Tearing, ciliary muscle spasm, loss of accommodation and ocular pain... Mydriasis...sometimes seen...probably due to sympatho-adrenal discharge. 5. Loss of muscle coordination, slurring of speech, fasciculations and twitching of muscles (particularly of tongue and eyelids), and generalized profound weakness. 6. Mental confusion, disorientation and drowsiness. 7. Difficulty in breathing, excessive secretion of saliva and of respiratory tract mucus, oronasal frothing, cyanosis, pulmonary rales and rhonchi and hypertension (presumably due to asphyxia). 8. Random jerky movements, incontinence, convulsions, and coma. 9. Death primarily due to respiratory arrest arising from failure of respiratory center, paralysis of respiratory muscles, intense bronchoconstriction or all three. /Parathion/

An estimated BCF of 1 was calculated for mipafox(SRC), determined from a water solubility of 80,000 mg/L(1) and a regression-derived equation(2). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The Henry's Law constant for mipafox is estimated as 3.0X10-9 atm-cu m/mole(SRC) derived from its vapor pressure, 0.001 mm Hg(1), and water solubility, 80,000 mg/L(2). This Henry's Law constant indicates that mipafox is expected to be essentially nonvolatile from water surfaces(3). Mipafox's estimated Henry's Law constant indicates that volatilization from moist soil surfaces is not expected to occur(SRC). Mipafox is not expected to volatilize from dry soil surfaces(SRC) based upon its vapor pressure(1).

/LABORATORY ANIMALS: Acute Exposure/ Mipafox produces demyelinating lesions in spinal cord and peripheral nerves. In...experimental animals, after apparent recovery from... attack of acute poisoning, muscular weakness has later developed... Should lesions be found, these are usually secondary to symptoms, eg pulmonary edema, asphyxia, gastroenteritis, etc.

/LABORATORY ANIMALS: Acute Exposure/ ... This study assesses the occurrence of the necrotizing myopathy in rats in relation to the clinical course and the acetylcholinesterase (AChE) inhibition after poisoning with organophosphates representative for each of the major types of organophosphate-related neurotoxicity. Marked differences are noted in the duration of cholinergic symptoms and of AChE inhibition after either paraoxon and mipafox, or fenthion poisoning. The necrotizing myopathy begins shortly after the initial decline in AChE activity with all organophosphates studied. Maximal muscle involvement occurs within the first 2 days of the poisoning with all organophosphates studied. The myopathy is not aggravated by a further decline in AChE activity in fenthion poisoning.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Adult male albino mice were given single subcutaneous injections of either mipafox (110 mumol/kg) or ecothiopate (0.5 mumol/kg), two organophosphorus compounds (OPs). Acetylcholinesterase activity was measured in the soleus (slow-twitch) and extensor digitorum longus (EDL; fast-twitch) muscles. At 7 and 28 days after dosing, in vitro electrophysiological measurements were carried out in the soleus and EDL. Action potentials and end-plate potentials were evoked at 30 Hz and recorded intracellularly from single muscle fibers. The amplitudes, time course, and latencies of these potentials were measured and the variability (jitter) of latencies was calculated. Recordings after mipafox were also made with 3-Hz stimulation. Acetylcholinesterase activity was inhibited by mipafox (65% in the soleus; 76% in the EDL) and ecothiopate (59% in the soleus; 42% in the EDL). Mipafox and ecothiopate both increased postjunctional (muscle action potential) jitter in the soleus and EDL at 7 days after dosing. Organophosphates caused an increase in end-plate potential amplitudes in the soleus. Mipafox caused an increase in prejunctional (end-plate potential) jitter at 28 days after dosing in both muscles. A single dose of ecothiopate also caused an increase in prejunctional jitter at 28 days in the soleus. The OP-induced increase in jitter was different at different frequencies of stimulation.

/LABORATORY ANIMALS: Neurotoxicity/ Hens treated with Mipafox (10 mg/kg, sc), daily for 10 days exhibited severe, moderate and no ataxia respectively on 14th day after the start of exposure. The neurotoxic esterase (NTE) activity was significantly inhibited in the brain, spinal cord and platelets of hens treated with mipafox or sarin whereas no change was noticed with parathion treatment. All three compounds significantly inhibited acetylcholinesterase (AChE) activity in the platelets. Spinal cord of hens treated with mipafox, sarin or parathion showed axonal degeneration heavy, moderate and none respectively.

The rate constant for the vapor-phase reaction of mipafox with photochemically-produced hydroxyl radicals has been estimated as 9.2X10-11 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 4.2 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Mipafox is reported to hydrolyze slowly under environmental conditions; a half life of 200 days was observed at pH 6(2). Mipafox does not contain chromophores that absorb at wavelengths >290 nm and therefore would not be expected to be susceptible to direct photolysis by sunlight(SRC).

Occupational exposure and general population exposure should be low or non-existent since mipafox is no longer produced or used. In the past, mipafox was applied directly to plants as an insecticide and exposure to this compound was primarily by inhalation and dermal contact. (SRC)

Mipafox's former production and use as an insecticide resulted in its direct release to the environment. If released to air, a vapor pressure of 0.001 mm Hg at 15 °C indicates mipafox will exist solely as a vapor in the ambient atmosphere. Vapor-phase mipafox 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 4.2 hours. Mipafox does not absorb light with wavelengths >290 nm and therefore would not be expected to be susceptible to direct photolysis by sunlight. If released to soil, mipafox is expected to have very high mobility based upon an estimated Koc of 8.8. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 6.3X10-10 atm-cu m/mole. Mipafox is not expected to volatilize from dry soil surfaces based upon its vapor pressure. If released into water, mipafox 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 1 suggests the potential for bioconcentration in aquatic organisms is low. Mipafox is reported to hydrolyze slowly; under environmental conditions a half life of 200 days was observed at pH 6. Occupational exposure and general population exposure should be low or non-existent since currently mipafox is no longer produced or used in the US (May, 2005). In the past, mipafox was applied directly to plants as an insecticide and exposure to this compound was primarily by inhalation and dermal contact. (SRC)

Used as an insecticide; [Merck Index] Used in neurotoxicology studies; [HSDB]

Not used in the US; [HSDB] This chemical ingredient is not found in any products. [NPIRS]

Farming (Pesticides) [Category: Industry]

For mipafox (USEPA/OPP Pesticide Code: 356300) there are 0 labels match. /SRP: Not registered for current use in the U.S., but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./

Insecticide /SRP 2005: Former use/

Investigative chemical for neurotoxicology studies

By reaction of isopropylamine with POCl3 in inert anhydrous solvent & treatment of product with strong aqueous solution of potassium or ammonium fluoride.

Pound et al, GB 688787 (1953 to Fisons)

Has been withdrawn from market being suspect as cause of paralysis of two operators...

/It is/ absorbed & translocated by plant which is rendered systemically insecticidal to sap-feeding insects & mites.