Animals In studies on slow lorises (Nyticebus coucang coucang), numerous chronic effects observed from topical applications. Mammalian placental development were also negatively affected. Metabolism Although TOCP is mainly excreted through urine and feces, it is partially metabolized by the hepatic cytochrome P450 system. Pathways include hydroxylation at one or more methyl groups, dearylation (removal of a o-cresyl group) and conversion of the hydroxymethyl groups to an aldehyde or a carboxylic acid. The first step results in a saligenin cyclic o-tolyl<unk>  (SCOTP) intermediate, a neurotoxin. To the right, the first step of TOCP metabolism is depicted by means of chemical structures. This intermediate is able to inhibit neuropathy target esterase (NTE) and results in the classic organophosphate-induced delayed neuropathy (OPIDN). In tandem, TOCP exerts physical damage by causing axonal destruction and myelin disintegration within specialized cells that transmit nerve impulses (neurons). In addition to the formation of SCOTP, the interactions between TOCP and two different human cytochrome P450 complexes (1A2 and 3A4) can further produce 2-(ortho-cresyl)-4H-1,2,3-benzodioxaphosphoran-2-one (CBDP). This metabolite can bind to butyrylcholinesterase (BuChE) and/or acetylcholinesterase (AChE). Binding to BuChE results in no adverse effects, for its typical role is to covalently bind to organophosphate poisons and detoxify them by inactivation. The dangers in metabolizing TOCP to CBDP occur when its potential to bind to AChE become imminent, for inactivation of the enzyme in nerve synapses can be lethal. The enzyme plays a tantamount role in terminating nerve impulse transmission "by hydrolyzing the neurotransmitter acetylcholine." Upon inactivation, acetylcholine can no longer be broken down in the body and results in uncontrollable muscle spasms, paralyzed breathing (bradycardia), convulsions, and/or death. Luckily, TOCP is considered a weak AChE inhibitor. Onset & Treatment In humans, the first symptoms are weakness/paralysis of the hands and feet on both sides of the body due to damage to the peripheral nervous system (polyneuropathy) and a sensation of pins-and-needles (paraesthesia). Onset typically occurs between 3–28 days from initial exposure. If ingested, this can be preceded by gastrointestinal symptoms that include nausea, vomiting, and diarrhea. Rates of metabolism vary by species and by individual; some people developed severe polyneuropathy after ingesting 0.15g of TOCP, whereas others have been reported asymptomatic after 1-2g. Though death is uncommon in acute exposure cases, the result of paralysis can last for months or years due to differences in gender, age, and route of exposure. The cardinal treatment is physical therapy to restore the use of the hands and feet, though it can take up to 4 years to only regain a fraction of motor control. Exposure to TOCP has been characterized by a list of observations: * Cholinesterase levels will remain unchanged or show no significant changes. * Electromyography will show partial or complete reactions of degeneration. * An increase of protein in cerebrospinal fluid. * Swelling of the parotid glands (non-tender). References
Tricresyl phosphate
Disufenton sodium
Dotinurad
Selenium disulfide
Diatrizoate
Aluminum chloride hexahydrate
Ferric maltol
Sodium oxybate