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Activity: Acaricide, Insecticide (organophosphate)
Note: WHO: Believed to be obsolete or discontinued for use as pesticides.
Structure:

Adverse Effects:
Ataxia
Brain
CNS
Sciatic Nerve
Spinal Cord

Ataxia (click on for all fluorinated pesticides)

The ability of sarin (107448) to induce delayed neurotoxicity was examined in mice. Female Swiss-albino-mice were exposed to 5mg/m3 sarin vapor 20 minutes/day for 10 days. Other mice were injected subcutaneously with 2.5mg/kg mipafox (371868) daily for 10 days. Mice were observed for clinical signs of toxicity for 14 days starting after the first sarin or mipafox exposure. They were killed on day 14. Brain and spinal cord tissues, and blood platelets were assayed for neurotoxic-esterase (NTE) activity. Spinal cord sections were prepared and examined for histopathological changes. Mice exposed to sarin developed muscular weakness in the limbs and ataxia on day 14. Mipafox exposed mice developed severe ataxia. Both sarin and mipafox inhibited brain, spinal cord, and platelet NTE activity. Sarin was less potent than mipafox. Sarin and mipafox induced spinal cord axonal degeneration. The degree of degeneration was greater in mipafox treated mice. Sarin also caused focal axonal degeneration in the lateral branches of the spinal cord. The authors conclude that sarin seems capable of inducing delayed neurotoxicity in mice following repeat inhalation exposure.
Ref: Husain K et al. (1993). Delayed Neurotoxic Effect of Sarin in Mice after Repeated Inhalation Exposure. Journal of Applied Toxicology, Vol. 13, No. 2, pages 143-145. As cited on Toxnet.

DAILY ADMIN OF MIPAFOX TO RATS FOR 35 DAYS PRODUCED ATAXIA & REDN IN LEVEL OF DOPAMINE IN CORPUS STRIATUM. [FREED VH ET AL; ROLE OF STRIATAL DOPAMINE IN DELAYED NEUROTOXIC EFFECTS OF ORGANOPHOSPHORUS COMPOUNDS; EUR J PHARMACOL 35 (1): 229-32 (1976)]
Ref: TOXNET profile for Mipafox from Hazardous Substances Data Base.
http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB

Brain (click on for all fluorinated pesticides)

There are many abstracts pertaining to Mipafox effects on brain - see
http://www.fluoridealert.org/pesticides/Mipafox.PubMed.htm

Excerpts: ... At ten times the concentration of mipafox that causes a 50% inhibition of NTE (5x10-5 M/day) mipafox was found to significantly decrease neurite length in differentiated cells while paraoxon and OPH-hydrolyzed paraoxon at the same concentration did not.
... While some organophosphorus (OP) compounds including paraoxon produce acute toxicity through acetylcholinesterase inhibition, others such as mipafox produce OP-induced delayed neurotoxicity (OPIDN), which is characterized anatomically by Wallerian-type "dying back" neuropathy in the axon and myelin.
... Protein expression of NF200 was shown to be a new biomarker by which the neurotoxic effects of mipafox and paraoxon on SY5Y cells were distinguishable at the molecular level.
... The current study shows that organophosphorus compounds produce not only antiesterase activity but also modifications in protein. Evidence presented suggests that mipafox caused shortening of neurites in differentiated SY5Y cells by a degeneration process, whereas paraoxon inhibited neurite growth in the cells.
Ref: Research Project (April 2001 - April 2006): Organophosphate Insecticide Damage to the Mature and Developing Nervous Systems: in Vitro Systems for Detection and Remediation. Principal Investigator: E. Tiffany-Castiglioni. Texas A&M University.
http://www.tard.state.tx.us/index.php?mode=Listing&rl_id=639

..ACETYLCHOLINESTERASE INHIBITOR, LIKE PARATHION. AFTER ACUTE PHASES OF POISONING, DEGENERATIVE LESIONS MAY BECOME APPARENT IN CENTRAL & PERIPHERAL NERVOUS SYSTEMS. [Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976.,p. II-196]
Ref. Hazardous Substances Data Bank for MIPAFOX CASRN: 371-86-8. Available at Toxnet.

... In a study of alkyl phosphate poisoning, Pasi and Leuzinger came to the conclusion that delayed lesions only occur, if at all, after severe cerebral anoxia [176]. As regards anatomical changes in the brain (demyelination), these delayed lesions correspond to those caused by peripheral neuropathy in acute and chronic ortho-tricresyl phosphate poisoning and are confined to fluorine- containing alkyl phosphates - for example, mipafox, DFP, sarin and soman. A synoptic evaluation of 536 civilian cases of alkyl phosphate poisoning made by the above-mentioned authors led them to the conclusion that acute poisoning by civilian alkyl phosphates did not result in delayed lesions. It should be noted, however, that their period of observation of two to three years was inadequate for investigations of delayed lesions beside the scale of Spiegelberg and others [p 40].
Ref: Delayed Toxic Effects of Chemical Warfare Agents. A SIPRI (Stockholm international Peace Research Institute) Monograph. 1975. ISBN 91-85114-29-4.
http://projects.sipri.se/cbw/research/cw-delayed.pdf

PubMed abstract: A single injection of mipafox was administered to both Long-Evans hooded rats and White Leghorn hens in dosages which inhibited the activity of brain neurotoxic esterase 30-50%, 60-80%, or greater than 80% four hr after intoxication. All animals were monitored for clinical evidence of organophosphorus induced delayed neuropathy for 21 days, euthanatized, and regions of the nervous system were histologically evaluated. Only hens manifested clinical signs of neuropathy; however, light and electron microscopic lesions were present in the nervous systems of both species. In rats, these lesions were well developed in only the highest dosage group and confined to the rostral level of the fasciculus gracilis in the medulla oblongata. Swollen axons containing a single vacuole filled with flocculent material were the most prominent lesion in rats. Hens manifested more extensive and varied fiber breakdown in multiple spinal cord tracts, with the intensity of degeneration increasing with increasing dosages of mipafox. Both marked Wallerian-like degeneration and swollen axons filled with aggregates of cellular debris were observed in the nervous systems of hens. This study indicates that both rats and hens are susceptible to OPIDN. However, there are qualitative and quantitative differences in both clinical manifestations and histologic appearances between the two species.
Ref: Comparative dose-response studies of organophosphorus ester-induced delayed neuropathy in rats and hens administered mipafox; by Dyer KR, Jortner BS, Shell LG, Ehrich M. Neurotoxicology 1992 Winter;13(4):745-55.

PubMed abstract: Adult male Long-Evans rats and White Leghorn hens were given 30 mg/kg mipafox ip. Administration of this organophosphorus ester resulted in > or = 89% inhibition of brain and spinal cord neurotoxic esterase activity in both species 4 hr after dosing. Our sequential, comparative study of the bilateral mipafox-induced neuropathy in the medulla and cervical spinal cord in hens and rats demonstrated that the rats had well-developed, vacuolar axonopathic lesions in the fasciculus gracilis by post-dosing day 7. Severely affected rats with such lesions were noted through day 21, but not subsequently (days 28 and 35). The hen had a slower developing, but more severe, consistent and longer lasting neuropathy than the rat. In these birds, lesions in the medulla and rostral cervical spinal cord levels were more extensive, involving large regions of both the spinocerebellar tracts and fasciculus gracilis. Neuropathic changes, including myelinated fiber axonopathy and Wallerian-like degeneration, were prominent from days 14 - 35 in hens, and were associated with prominent gliosis in the later stages.
Ref: Comparative evolution of mipafox-induced delayed neuropathy in rats and hens; by Carboni D, Ehrich M, Dyer K, Jortner BS. Neurotoxicology 1992 Winter;13(4):723-33.

Definitions:

Fasciculus gracilis.
White matter in the dorsal, medial area of the spinal cord. It forms the entire dorsal column in the lumbar and sacral levels and the medial division of the dorsal column in the thoracic and cervical regions. It carries sensory information from the lower extremities. In the thoracic and cervical regions it is located between the fasciculus cuneatus and the dorsal median fissure. In the lumbar and sacral regions it is found between the dorsal horn and the dorsal median fissure.

Gliosis.
The production of a dense fibrous network of neuroglia; includes astrocytosis, which is a proliferation of astrocytes in the area of a degenerative lesion.

Gliosis - excerpt from PubMed Abstract:
... Our results show that chronic gliosis is associated with altered processing of the amyloid precursor protein in vivo and thus may initiate or exacerbate pathological changes associated with Alzheimer's disease.
Ref: Bates KA et al (2002). Chronic gliosis triggers Alzheimer's disease-like processing of amyloid precursor protein. Neuroscience: 113(4):785-96.

Medula
lower or hindmost part of the brain; continuous with spinal cord; (`bulb' is an old term for medulla oblongata); "the medulla oblongata is the most vital part of the brain because it contains centers controlling breathing and heart functioning"

Abstract: The effects of multiple low doses of ecothiopate (513100), paraoxon (311455), and mipafox (371868) on organophosphate target enzymes in the brain and diaphragm were studied in mice. Male albino-mice were injected subcutaneously once with 0 or 110 micromoles per kilogram (micromol/kg) mipafox, 0.5micromol/kg ecothiopate, or 1.5micromol/kg paraoxon or with 0 or 44micromol/kg mipafox, 0.2micromol/kg ecothiopate, or 0.6micromol/kg paraoxon daily for 5 days or 27.5micromol/kg mipafox daily for 8 day s. The mice were killed 3 hours (hr) after the single dose or 3 or 24hr after each of the multiple doses and the brain and diaphragms were removed... Mipafox and paraoxon inhibited brain AChE activity by 55 and 73%, respectively... Only mipafox inhibited brain NTE activity, by 66%. Brain AChE activity was progressively inhibited by 17 to 46% by multiple dosing with 27.5micromol/kg mipafox, by 23 to 49% by multiple injection with 44micromol/kg mipafox, and by 20 to 55% by multiple dosing with paraoxon... Mipafox also produced a progressive inhibition of brain NTE activity, the cumulative inhibitory effect, 74 and 76%, being similar after the two dosing protocols. The authors conclude that exposure to multiple low doses of mipafox, ecothiopate, and paraoxon produces additive inhibition of AChE activity. These results have implications for humans as humans are generally exposed to low levels of organophosphates for extended periods of time.
Ref: Williams FM et al (1997. The Effects of Multiple Low Doses of Organophosphates on Target Enzymes in Brain and Diaphragm in the Mouse. Human and Experimental Toxicology, Vol. 16, No. 2, pages 67-71.
Abstract available at
http://www.fluorideaction.org/pesticides/mipafox.pubmed.htm

CNS (click on for all fluorinated pesticides)

There are seversal abstracts on this effect - see
http://www.fluorideaction.org/pesticides/mipafox.pubmed.htm

CHOLINESTERASE INHIBITOR.
[The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 889]
Ref: TOXNET profile for Mipafox from Hazardous Substances Data Base.
http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB

Note: What is Cholinesterase? An enzyme produced by the body. Essential to the Central Nervous System (CNS). Lack of Cholinesterase can cause CNS confusion. Symptoms of decreased cholinesterase: Headaches Dizziness Nausea Abdominal pain Anxiety Constricted pupils Muscle twitch or weakness Shortness of breath Diarrhea Convulsions Coma
Reference

Abstract: Chick embryo dorsal root ganglia (DRG) cultures were used to explore early pathological events associated with exposure to neuropathy-inducing organophosphorus (OP) compounds. This approach used an in vitro neuronal system from the species that provides the animal model for OP-induced delayed neuropathy (OPIDN). DRG were obtained from 9-day-old chick embryos, and grown for 14 days in minimal essential medium (MEM) supplemented with bovine and human placental sera and growth factors. Cultures were then exposed to 1 microM of the OP compounds phenyl saligenin phosphate (PSP) or mipafox, which readily elicit OPIDN in hens, paraoxon, which does not cause OPIDN, or the DMSO vehicle. The medium containing these toxicants was removed after 12 h, and cultures maintained for 4-7 days post-exposure. Morphometric analysis of neurites was performed by inverted microscopy, which demonstrated that neurites of cells treated with mipafox or PSP but not with paraoxon had decreased length-to-diameter ratios at day 4 post-exposure. Ultrastructural alterations of neurons treated with PSP and mipafox included dissolution of microtubules and neurofilaments and degrading mitochondria. Paraoxon-treated and DMSO control neuronal cell cultures did not show such evident ultrastructural changes. This study demonstrates that chick DRG show pathological changes following exposure to neuropathy-inducing OP compounds.
Ref: Morphological effects of neuropathy-inducing organophosphorus compounds in primary dorsal root ganglia cell cultures; by Massicotte C, Jortner BS, Ehrich M. Neurotoxicology. 2003 Dec;24(6):787-96.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14637373

Abstract: Short term clinical and neuropathological effects induced by tri-ortho-tolyl-phosphate (78308) (TOTP), diisopropyl-fluorophosphate (55914) (DFP), phenyl-saligenin-phosphate (4081236) (PSP), mipafox (371868), malathion (121755), dichlorvos (62737), and carbaryl (63252) were studied in rats. Male Long-Evans-rats were administered 300 to 1000mg/kg TOTP or 300 to 2000mg/kg malathion orally, injected intramuscularly with 5 to 24mg/kg PSP, injected subcutaneously with 1 to 3mg/kg DFP, or injected intraperitoneally with 3 to 30mg/kg mipafox or dichlorvos or 30 to 160mg/kg carbaryl. The rats were also treated with atropine-sulfate to protect against cholinergic symptoms. Selected rats were killed 4 hours after DFP, PSP, mipafox, dichlorvos, and carbaryl or 48 hours after TOTP and malathion and the brains and spinal cords were removed and assayed for acetylcholinesterase (AChE) and neurotoxic-esterase (NTE) activity. The remaining rats were weighed and evaluated on a functional observational battery (FOB) that measured motor activity and responses to being handled or approached 1, 7, 14, and 21 days after dosing. The rats were then killed and the brains, spinal cords, and tibial nerve branches leading to the gastrocnemius muscle were examined for histopathological changes. The highest doses of all compounds except PSP induced transient cholinergic symptoms and caused 8.3 to 61% mortality within 48 hours. The highest doses of TOTP, DFP, and malathion significantly decreased body weight after 14 days. All compounds caused dose related inhibitions of brain and spinal cord AChE and NTE activity. DFP was the most potent and PSP the least potent. All compounds induced significant changes in FOB parameters related to behavioral and central nervous system excitability 21 days after dosing. Mipafox, PSP, dichlorvos, and carbaryl induced these changes 1 day after dosing. TOTP, DFP, PSP, and mipafox caused mild to moderate myelinated fiber degeneration in the rostral fasciculus gracilis 21 days after dosing. Mipafox was the most potent. DFP also induced Wallerian like degeneration in the tibial nerve branches. Dichlorvos, malathion, and carbaryl did not cause any neurological changes. The authors conclude that some cholinesterase inhibitors cause behavioral changes even after cholinergic signs are no longer evident.
Ref: Short-Term Clinical and Neuropathologic Effects of Cholinesterase Inhibitors in Rats; by Ehrich M, Shell L, Rozum M, Jortner BS. Journal of the American College of Toxicology, Vol. 12, No. 1, pages 55-68, 1993.

Abstract: Various structurally unrelated chemicals [2,5 hexandione, acrylamide, organophosphates like mipafox, beta,beta iminodipropionnitrile (IDPN), 3-nitropropionic acid (3-NP), potassium cyanide (KCN), paraquat, and NMDA (N-methyl-D-apartic acid)] are known to cause degenerative damage of the peripheral or central nervous system. Differentiated neuronal cell cultures obtained from fetal rats have been used to differentiate the mechanisms underlying this type of neurotoxicity. Cytotoxicity as measured by a viability assay was not sensitive enough and had to be supplemented by further endpoints covering effects on cytoskeleton and on the energy state of the cells [glucose consumption, mitochondrial membrane potential and adenosine 5'-triphosphate (ATP) concentration]. Compounds like the delayed neurotoxic organophosphates, exert a selective direct effect on cytoskeleton elements in this model at concentrations distinctly below cytotoxic concentrations. Other compounds, like KCN, paraquat, and 3-NP selectively disrupt the balance between energy supply and demand of the neurons either by interacting with mitochondrial respiration or glycolysis. For these compounds cytoskeletal damage seemed to be secondary to the energy depletion. For NMDA, 2,5 hexandione and acrylamide, both mechanisms may contribute to the neuronal damage. In conclusion, primary cortical neuronal cultures of the rat are well suited to detect a neurotoxic potential and to differentiate its underlying mechanisms. Damage of the cytoskeleton may be considered as an endpoint mechanistically related to degenerative neuropathic effects.
Ref: Schmuck G et al. (2000). Rat cortical neuron cultures: an in vitro model for differentiating mechanisms of chemically induced neurotoxicity. In Vitr Mol Toxicol; Spring;13(1):37-50.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10900406&dopt=Abstract

Abstract: This study compares two direct-acting neuropathy target esterase (NTE) inhibitors (mipafox and 2-octyl-4H-1,3,2-benzodioxophosphorin 2-oxide (OBDPO)), a metabolic precursor to an NTE inhibitor (tri-o-cresyl phosphate or TOCP) and a potent acetylcholinesterase inhibitor (chlorpyrifos oxon or CPO) for their effects on outgrowth of neurite-like and cell processes and on viability in differentiated cultured cells (rat adrenal pheochromocytoma (PC-12) and brain glial tumor (C6)). The direct-acting NTE inhibitors block process outgrowth by 50% or more at 50-100 microM for OBDPO and 100-200 microM for mipafox, well below their cytotoxic levels (EC50 values, 445-474 microM for OBDPO and 1021-1613 microM for mipafox). In contrast, the effects on process development for TOCP and CPO parallel their cytotoxicity. These findings suggest that inhibition of neurite-like and cell process outgrowth by OBDPO and mipafox may be associated with NTE inhibition.
Ref: Li W et al. (2000). Organophosphorus neuropathy target esterase inhibitors selectively block outgrowth of neurite-like and cell processes in cultured cells. Toxicol Lett; Sep 15;98(3):139-46
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9788582&dopt=Abstract

Sciatic Nerve (click on for all fluorinated pesticides)

Abstract: Abstract: Bioclinical effects induced by local application of neuropathic organophosphates to the sciatic nerve were studied in adult red-hens. Diisopropyl-phosphorofluoridate (55914) (DFP), mipafox (371868), cresylsaligenyl-phosphate (CSP), or phenylsaligenyl-phosphate (4081236) (PSP) were applied locally to 1 or 1.5 centimeter segments of the common trunk of surgically exposed sciatic nerves in one leg of each hen. Doses ranged up to 1790, 17500, 108, or 526 micrograms (microg), respectively. The contralateral leg served as the control. Fifteen minutes later, the treated segments, the adjacent proximal and distal portions, and the most distal segments of the peroneal branch were dissected out and assayed for neuropathy-target-esterase (NTE) activity. DFP and mipafox caused greater than 90% inhibition of NTE activity in the treated sciatic nerve segments. A 40% inhibition of NTE activity was induced by DFP and mipafox in the adjacent proximal and distal segments. Less than 20% NTE inhibition was induced in the terminal segments. PSP and CSP did not significantly affect sciatic NTE activity. Since only DFP and mipafox significantly inhibited NTE activity these were used to investigate clinical symptomatology and histopathological changes induced in the sciatic nerve. Hens with surgically exposed sciatic nerves were treated locally in one or both legs with 27 to 110microg DFP or 18 to 182microg mipafox. Some hens were pretreated with 30mg/kg phenylmethanesulfonyl-fluoride (PMSF) subcutaneously. Hens were observed for clinical signs of toxicity for 15 to 25 days then killed on day 25. Peroneal nerves were removed and examined for histopathological changes. All hens treated in both legs with DFP or mipafox lost the avian retraction reflex. Only birds treated with the maximum DFP or mipafox doses in both legs developed gait abnormalities. Following application to one leg only, hens treated with 110microg DFP showed loss of the avian retraction reflex. No clinical signs of toxicity were seen in birds pretreated with PMSF. DFP or mipafox caused axon swelling, accumulation of endoplasmic reticulum, and intraaxonal and intramyelinal vacuolation. The authors conclude that the peripheral neuropathological effects of locally applied DFP or mipafox appear to be mediated by their effects on NTE.
Ref: Toxicology and Applied Pharmacology, Vol. 117, No. 2, pages 218-225, 31 references, 1992.
Local Application of Neuropathic Organophosphorus Compounds to Hen Sciatic Nerve: Inhibition of Neuropathy Target Esterase and Peripheral Neurological Impairments. by Carrera V, Barril J, Mauricio M, Pellin M, Vilanova E. -from Toxnet.

Abstract. Neuropathy target esterase (NTE) is a protein suggested to be involved in the initiation mechanism of organophosphorus-induced delayed neuropathy (OPIDP). We previously described two different forms of NTE activity in hen sciatic nerve: a particulate form (P-NTE) representing 40-50% of total NTE activity in sciatic nerve, and a remaining soluble component (S-NTE). In brain tissue on the other hand, more than 90% of NTE activity was recovered as P-NTE. In this work we studied the in vivo inhibition of both NTE forms with different doses of mipafox and the results were compared with sensitivity to mipafox in vitro. The highest dose with no observable neuropathic effects (1.5 mg/kg mipafox p.o.) inhibited 33% P-NTE and 55% S-NTE activity. The difference between P-NTE and S-NTE activity was statistically significant (P < 0.001, n = 9). Higher doses (3 mg/kg) induced neuropathy and inhibited NTE more than 75%, but differences between P- and S-NTE were not significant (P > 0.5). The greater inhibition of S-NTE than P-NTE in vivo contrasts with the observation that S-NTE is less sensitive in vitro.
Ref: Toxicol Lett 1994 Mar;71(1):47-51 In vivo inhibition by mipafox of soluble and particulate forms of organophosphorus neuropathy target esterase (NTE) in hen sciatic nerve. Carrera V, Diaz-Alejo N, Sogorb MA, Vicedo JL, Vilanova E.

Abstract: Considerable evidence exists suggesting that the so-called neuropathy target esterase (NTE) is involved in the mechanisms responsible for organophosphorus-induced delayed polyneuropathy (OPIDP). Earlier studies in the adult hen, the habitually employed experimental model in OPIDP, have shown that most NTE activity in the brain is centered in particulate fractions, whereas approximately 50% of this activity in the sciatic nerve is encountered in soluble form, with the rest being particulate NTE. In the present work, we have studied the particulate and soluble fractional distribution of paraoxon-resistant phenylvalerate esterase activity (B activity), paraoxon- and mipafox-resistant phenylvalerate esterase activity (C activity), and NTE activity (B-C) according to ultracentrifugation criteria (100,000 g for 1 h). To this effect, two sensitive (adult hen and cat) and two scarcely sensitive (rat and chick) models were used. In all four experimental models, the distribution pattern was qualitatively similar: B activity and total NTE were much greater in brain (900-2,300 nmol/min/g of tissue) than in sciatic nerve (50-100 nmol/min/g of tissue). The proportion of soluble NTE in brain was very low (< 2%), whereas its presence in sciatic nerve was substantial (30-50%). The NTE/B ratio in brain was high for the particulate fraction (> 60%) and low in the soluble fraction (7-30%); in sciatic nerve the ratio was about 50% in both fractions.(ABSTRACT TRUNCATED AT 250 WORDS)
Ref: J Neurochem 1993 Dec;61(6):2164-8. Soluble and particulate organophosphorus neuropathy target esterase in brain and sciatic nerve of the hen, cat, rat, and chick. Tormo N, Gimeno JR, Sogorb MA, Diaz-Alejo N, Vilanova E.

Spinal Cord (click on for all fluorinated pesticides)

...SOME CHOLINESTERASE-INHIBITING ORGANOPHOSPHORUS CMPD 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. [Hamilton, A., and H. L. Hardy. Industrial Toxicology. 3rd ed. Acton, Mass.: Publishing Sciences Group, Inc., 1974. 358]
Ref: TOXNET profile for Mipafox from Hazardous Substances Data Base.

Short term clinical and neuropathological effects induced by tri-ortho-tolyl-phosphate (78308) (TOTP), diisopropyl-fluorophosphate (55914) (DFP), phenyl-saligenin-phosphate (4081236) (PSP), mipafox (371868), malathion (121755), dichlorvos (62737), and carbaryl (63252) were studied in rats. Male Long-Evans-rats were administered 300 to 1000mg/kg TOTP or 300 to 2000mg/kg malathion orally, injected intramuscularly with 5 to 24mg/kg PSP, injected subcutaneously with 1 to 3mg/kg DFP, or injected intraperitoneally with 3 to 30mg/kg mipafox or dichlorvos or 30 to 160mg/kg carbaryl. The rats were also treated with atropine-sulfate to protect against cholinergic symptoms. Selected rats were killed 4 hours after DFP, PSP, mipafox, dichlorvos, and carbaryl or 48 hours after TOTP and malathion and the brains and spinal cords were removed and assayed for acetylcholinesterase (AChE) and neurotoxic-esterase (NTE) activity. The remaining rats were weighed and evaluated on a functional observational battery (FOB) that measured motor activity and responses to being handled or approached 1, 7, 14, and 21 days after dosing. The rats were then killed and the brains, spinal cords, and tibial nerve branches leading to the gastrocnemius muscle were examined for histopathological changes. The highest doses of all compounds except PSP induced transient cholinergic symptoms and caused 8.3 to 61% mortality within 48 hours. The highest doses of TOTP, DFP, and malathion significantly decreased body weight after 14 days. All compounds caused dose related inhibitions of brain and spinal cord AChE and NTE activity. DFP was the most potent and PSP the least potent. All compounds induced significant changes in FOB parameters related to behavioral and central nervous system excitability 21 days after dosing. Mipafox, PSP, dichlorvos, and carbaryl induced these changes 1 day after dosing. TOTP, DFP, PSP, and mipafox caused mild to moderate myelinated fiber degeneration in the rostral fasciculus gracilis 21 days after dosing. Mipafox was the most potent. DFP also induced Wallerian like degeneration in the tibial nerve branches. Dichlorvos, malathion, and carbaryl did not cause any neurological changes. The authors conclude that some cholinesterase inhibitors cause behavioral changes even after cholinergic signs are no longer evident.
Ref: Ehrich M et al. (1993). Short-Term Clinical and Neuropathologic Effects of Cholinesterase Inhibitors in Rats. Journal of the American College of Toxicology, Vol. 12, No. 1, pages 55-68. As cited at Toxnet.

Definitions: Fasciculus gracilis.
White matter in the dorsal, medial area of the spinal cord. It forms the entire dorsal column in the lumbar and sacral levels and the medial division of the dorsal column in the thoracic and cervical regions. It carries sensory information from the lower extremities. In the thoracic and cervical regions it is located between the fasciculus cuneatus and the dorsal median fissure. In the lumbar and sacral regions it is found between the dorsal horn and the dorsal median fissure.