Cyclosarin

180.16

180.16

2810

DTXSID00861875

Colorless liquid

log Kow = 1.67 (est)

1.13

-30.0 °C|-30 °C

239.0 °C|239 °C

In water, 3,700 mg/L at 20 °C

0.04 mmHg|0.044 mm Hg at 20 °C

6.2 (Air = 1)

Odorless|Agent GF is reported to have a sweet or musty odor of peaches

Henry's Law constant = 2.8X10-6 atm-cu m/mole at 20 °C (est)

Hydroxyl radical reaction rate constant = 6.7X10-11 cu cm/molecule-sec at 25 °C (est)

Likely hydrolyzed by water, rapidly hydrolyzed by dilute aqueous sodium hydroxide.

Sulfonates, Phosphonates, and Thiophosphonates, Organic

Water-Reactive

Acidic conditions produce hydrogen fluoride; alkaline conditions produce isopropyl alcohol and polymers. When heated to decomposition or reacted with steam, it emits very toxic fumes of fluorides and oxides of phosphorus. Slightly corrosive to steel. Hydrolyzed by water.

Principles and methods for destruction of chemical weapons: ... "Destruction of chemical weapons" means a process by which chemicals are converted in an essentially irreversible way to a form unsuitable for production of chemical weapons, and which in an irreversible manner renders munitions and other devices unusable as such. ... Each State Party shall determine how it shall destroy chemical weapons, except that the following processes may not be used: dumping in any body of water, land burial or open-pit burning. It shall destroy chemical weapons only at specifically designated and appropriately designed and equipped facilities. ... Each State Party shall ensure that its chemical weapons destruction facilities are constructed and operated in a manner to ensure the destruction of the chemical weapons; and that the destruction process can be verified under the provisions of this Convention.|SRP: Wastewater from contaminant suppression, cleaning of protective clothing/equipment, or contaminated sites should be contained and evaluated for subject chemical or decomposition product concentrations. Concentrations shall be lower than applicable environmental discharge or disposal criteria. Alternatively, pretreatment and/or discharge to a permitted wastewater treatment facility is acceptable only after review by the governing authority and assurance that "pass through" violations will not occur. Due consideration shall be given to remediation worker exposure (inhalation, dermal and ingestion) as well as fate during treatment, transfer and disposal. If it is not practicable to manage the chemical in this fashion, it must be evaluated in accordance with EPA 40 CFR Part 261, specifically Subpart B, in order to determine the appropriate local, state and federal requirements for disposal.

Reactivity: Most of the "G" series nerve agents decompose slowly in water. Raising the pH increases the rate of decomposition significantly. Reaction with dry bleach may produce toxic gases. /"G" Series Nerve Agents/

Gupta RC, ed. Handbook of Toxicology of Chemical Warfare Agents. Amsterdam: Academic Press (2009). This handbook provides in-depth information on chemical warfare agents and covers every aspect of deadly toxic chemicals used as weapons of mass destruction and employed in conflicts, warfare and terrorism.|National Research Council Subcommittee on Acute Exposure Guideline Levels Committee on Toxicology Division on Earth and Life Studies; Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol 3. 300 p. (2003). ISBN 0-309-51590-4 (PDF) National Academies Press, Washington, DC

Excerpt from ERG Guide 153 [Substances - Toxic and/or Corrosive (Combustible)]: Combustible material: may burn but does not ignite readily. When heated, vapors may form explosive mixtures with air: indoors, outdoors and sewers explosion hazards. Those substances designated with a (P) may polymerize explosively when heated or involved in a fire. Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form. (ERG, 2016)

Excerpt from ERG Guide 153 [Substances - Toxic and/or Corrosive (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 153 [Substances - Toxic and/or Corrosive (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: If this material is being used as a weapon, see ERG Table 1 - Initial Isolation and Protective Action Distances on the UN/NA 2810 datasheet. Otherwise 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 153 [Substances - Toxic and/or Corrosive (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)

Excerpt from ERG Guide 153 [Substances - Toxic and/or Corrosive (Combustible)]: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing that is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations where direct contact with the substance is possible. (ERG, 2016)|Nerve agent vapor is readily absorbed by inhalation and ocular contact and produces rapid local and systemic effects. The liquid is readily absorbed thorough the skin; however, effects may be delayed for several minutes to up to18 hours. Respiratory Protection: Pressure-demand, self-contained breathing apparatus (SCBA) is recommended in response situations that involve exposure to any nerve agent vapor or liquid. Skin Protection: Chemical-protective clothing and butyl rubber gloves are recommended when skin contact is possible because nerve agent liquid is rapidly absorbed through the skin and may cause systemic toxicity. /Nerve agents/|Recommendations for Personal Protective Equipment /PPE/ should be based on a site-based job hazard analysis of possible hazards including skin contact, air concentrations, heat stress, etc. All PPE should be used with appropriate additional administrative controls including medical surveillance, employee training, respirator fit-testing, and decontamination procedures to limit the potential for unforeseen adverse effects. /Nerve agents/|Personal Protective Requirements: "G" series nerve agents pose both a severe respiratory and severe contact hazard. Wear appropriate fully encapsulating protective gear with positive pressure self contained breathing apparatus (SCBA). Structural firefighters' protective clothing is recommended for fire situations only; it is not effective in spill or release events. Thickened agents pose a less significant vapor hazard but a much more significant contact hazard. /"G" Series Nerve Agents/|Protective equipment (self-contained breathing equipment or gas mask, barrier suit) must be used. ... Latex gloves are not adequate protection.

Fire: "G" series Nerve Agents may be volatilized during a fire or be spread by efforts to extinguish the fire. Agents may be decomposed by heat to produce other toxic and/or corrosive gases. In addition, "G" series Nerve Agents may react with steam or water during a fire to produce toxic and/or corrosive vapors. Hydrogen produced by the action of the corrosive vapors on metals or other corrodible materials may be present. /"G" Series Nerve Agents/

Protection: Evacuation: Immediately isolate an area around any liquid or solid contamination for at least 700 feet in all directions. If possible, identify the agent and develop a downwind hazard diagram (see Table 3.2). Adjust the initial isolation distance as appropriate. Based on the type of release, amount of material aerosolized, persistence of the agent and local conditions (e.g., weather, population density, time of day), shelter in place until the initial cloud passes may be the most appropriate course of action since timely evacuation of the threatened downwind population may not be possible. Depending on the persistence of the agent and the potential for condensation of agent from the cloud, evacuation of the threatened population after passage of the initial cloud may be appropriate. /"G" Series Nerve Agents/

SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning.|Responders should be trained and appropriately attired before entering the Hot Zone. If the proper personal protective equipment (PPE) is not available, or if the rescuers have not been trained in its use, call for assistance in accordance with local Emergency Operational Guides (EOG). ... /in the decontamination zone, rescuers/ should continue to wear the same level of protection as required in the Hot Zone. /Nerve Agents/|Victims whose skin or clothing is contaminated with liquid nerve agent can contaminate rescuers by direct contact or through off-gassing vapor.... Before transport, all casualties must be decontaminated. ...Rapid decontamination is critical to prevent further absorption by the patient and to prevent exposure to others. Decontaminable gurneys and back boards should be used if possible when managing casualties in a contaminated area. ... All victims must be decontaminated properly before entering the Support Zone. /Nerve Agents/|If contaminated patients arrive at the Emergency Department, they must be decontaminated before being allowed to enter the facility. Decontamination can only take place inside the hospital if there is a decontamination facility with negative air pressure and floor drains to contain contamination. Personnel should wear the same level of protection required in the Hot Zone. /Nerve Agents/|For more Preventive Measures (Complete) data for CYCLOSARIN (6 total), please visit the HSDB record page.

If ... THERE IS NO FIRE, go directly to the Table of Initial Isolation and Protective Action Distances /(see table below)/ ... to obtain initial isolation and protective action distances. IF THERE IS A FIRE, or IF A FIRE IS INVOLVED, go directly to the appropriate guide /(see guide(s) below)/ and use the evacuation information shown under PUBLIC SAFETY. /GF (when used as a weapon)/:|/GUIDE 153: SUBSTANCES - TOXIC AND/OR CORROSIVE (COMBUSTIBLE)/ Health: 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.|/GUIDE 153: SUBSTANCES - TOXIC AND/OR CORROSIVE (COMBUSTIBLE)/ Fire or Explosion: Combustible material: may burn but does not ignite readily. When heated, vapors may form explosive mixtures with air: indoors, outdoors, and sewers explosion hazards. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form.|/GUIDE 153: SUBSTANCES - TOXIC AND/OR CORROSIVE (COMBUSTIBLE)/ Public Safety: CALL Emergency Response Telephone Number ... 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. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate enclosed areas.|For more DOT Emergency Guidelines (Complete) data for CYCLOSARIN (9 total), please visit the HSDB record page.

The toxicity of agents GB and GF were basically additive when administered together by subcutaneous injection to mice.|The combined toxicity of sarin and cyclosarin does not indicate synergism...|Rhesus monkeys administered five times the LD50 but treated with atropine, pyridostigmine, and either 2-PAM or HI6 oxime all lived and had minimal nervous system changes.|A computer program (Q-test) was used to evaluate the combined toxic effects of nerve agent GF and its combined form with sarin (GB/GF) in mice. Efficacy of Jielin Injection, the 2-PAM-containing antidote used successfully in China for the treatment of organophosphate pesticide poisoning, was also evaluated and compared with HI-6 against single and combined poisonings. The two agents were basically additive in toxicity when combined. However, toxic signs (convulsions) appeared later in combined poisoning than after exposure to each agent alone. The protective ratio of Jielin Injection against GF poisoning was low but significantly higher when against poisoning by GB or combined agent. When HI-6 was substituted for 2-PAM, the antidote was more effective against poisoning by both single and combined agents. Results of in vitro reactivation of GF-inhibited human erythrocyte acetylcholinesterase by these oximes agreed with the in vivo antidotal efficacy.|For more Interactions (Complete) data for CYCLOSARIN (7 total), please visit the HSDB record page.

LCt50 /lethal concentration & time/ Rat (male) 181 mg-min/cu m (1minute exposure)|LCt50 /lethal concentration & time/ Rat (female) 110 mg-min/cu m (1minute exposure)|LD50 Rat sc 225 ug/kg|LD50 Mouse sc 400 ug/kg|For more Non-Human Toxicity Values (Complete) data for CYCLOSARIN (15 total), please visit the HSDB record page.

Children have several vulnerabilities putting them at increased toxicity from this class of chemical agents. A child's smaller mass alone reduces the dose needed to cause symptoms or lethality. For volatile nerve agents, children are especially at risk for respiratory toxicities due to their anatomic differences compared to adults. Their smaller airways can become compromised by the large amount of secretions and the bronchospasm caused by the agents. Also, a greater dose of nerve agent will be inhaled in children due to their higher respiratory rate and minute volumes. /Nerve Agents/

Cyclosarin's production may result in its release to the environment through various waste streams; its use as a chemical warfare nerve agent(1) will result in its direct release to the environment(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 56(SRC), determined from a structure estimation method(2), indicates that cyclosarin is expected to have high mobility in soil(SRC). Volatilization of cyclosarin from moist soil surfaces may be an important fate process(SRC), given an estimated Henry's Law constant of 2.8X10-6 atm cu m/mol(SRC), derived from its vapor pressure, 0.044 mm Hg(3) and water solubility of 3,700 mg/L(3). Volatilization from dry soil, moist soil, snow and other solid surfaces has been observed to occur with other similar G-type nerve agents (tabun, sarin and soman)(4-6) which indicate, by analogy, that volatilization is expected to be an important fate process for cyclosarin (nerve agent GF)(SRC). Cyclosarin hydrolyzes in water forming hydrofluoric and cyclohexylmethylphosphonic acids(7); although hydrolysis rates in soil are not available, estimated water hydrolysis half-lives on the order of a few hours-to-several days at 25 °C and pH 5-8(2) suggest that hydrolysis in moist soil will be an important fate process(SRC). Biodegradation data in soil were not available(SRC, 2013); however, biodegradation has been demonstrated under controlled conditions(8).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 56(SRC), determined from a structure estimation method(2), indicates that cyclosarin is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water may be an important environmental fate process(3), given an estimated Henry's Law constant of 2.8X10-6 atm cu m/mol(SRC), derived from its vapor pressure, 0.044 mm Hg(4) and water solubility of 3,700 mg/L(4). Using this Henry's Law constant and an estimation method(3), volatilization half-lives from a model river and model lake are 18 and 132 days, respectively(SRC). If released into natural waters or water systems, cyclosarin will likely degrade rapidly (less than 2 days) depending on cyclosarin volume and other environmental conditions(5). Cyclosarin hydrolyzes in water with the hydrolysis products being hydrofluoric and cyclohexylmethylphosphonic acids(6) which are unlikely to persist for more than a few days in an unprotected environment(6). Using a structure estimation method(6), the hydrolysis half-life of cyclosarin at 25 °C can be estimated to be 5 days at pH 6, 19 hours at pH7 and 2 hours at pH 8(SRC); these estimated half-lives are on the same order of magnitude as measured hydrolysis rates for sarin(7). According to a classification scheme(8), an estimated BCF of 6(SRC), from an estimated log Kow of 1.67(2) 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, 2013); however, biodegradation has been demonstrated under controlled conditions(9). [|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), cyclosarin, which has a vapor pressure of 0.044 Hg at 20 °C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase cyclosarin 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 6 hours(SRC), calculated from its rate constant of 6.7X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). The UV absorption spectrum of the structurally similar sarin in cyclohexane solution does not exhibit any absorption above 290 nm(4); therefore, by anaology cyclosarin is not expected to be susceptible to direct photolysis by sunlight(SRC).

The rate constant for the vapor-phase reaction of cyclosarin with photochemically-produced hydroxyl radicals has been estimated as 6.7X10-11 cu cm/molecule-sec at 25 °C(SRC), using a structure estimation method(1). This corresponds to an atmospheric half-life of about 6 hours(SRC) at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). If released into natural waters or water systems, cyclosarin will likely degrade rapidly (less than 2 days) depending on cyclosarin volume and other environmental conditions(2). Degradation in water occurs through hydrolysis with the hydrolysis products being hydrofluoric and cyclohexylmethylphosphonic acids(3) which are unlikely to persist for more than a few days in an unprotected environment(3). Using a structure estimation method(1), the hydrolysis half-life of cyclosarin at 25 °C can be estimated to be 5 days at pH 6, 19 hours at pH7 and 2 hours at pH 8(SRC); these estimated half-lives are on the same order of magnitude as measured hydrolysis rates for sarin(4). The UV absorption spectrum of the structurally similar sarin in cyclohexane solution does not exhibit any absorption above 290 nm(5); therefore, cyclosarin is not expected to degrade through direct photolysis in the environment(SRC).

An estimated BCF of 6 was calculated for cyclosarin(SRC), using an estimated log Kow of 1.67(1) and a regression-derived equation(1). According to a classification scheme(2), 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 cyclosarin can be estimated to be 56(SRC). According to a classification scheme(2), this estimated Koc value suggests that cyclosarin is expected to have high mobility in soil(SRC).

The Henry's Law constant for cyclosarin is estimated as 2.8X10-6 atm-cu m/mole(SRC) derived from its vapor pressure, 0.044 mm Hg(1), and water solubility, 3,700 mg/L(1). This Henry's Law constant indicates that cyclosarin is expected to volatilize from moist soil and water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 18 days(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 132 days(SRC). Volatilization from dry soil, moist soil, snow and other solid surfaces has been observed to occur with other similar G-type nerve agents (tabun, sarin and soman)(3-5) which indicate, by analog, that volatilization is expected to be an important fate process for cyclosarin (nerve agent GF)(SRC).

Occupational exposure to cyclosarin may occur through inhalation and dermal contact with this compound at workplaces where cyclosarin is produced or used. Occupational exposure and exposure to the general population to cyclosarin should be rare since this compound has been suggested as a chemical warfare agent, although apparently there has been no commercial production(1) in the US. The general population will not be exposed to cyclosarin unless it is used as a weapon; exposure to cyclosarin, if used as a weapon, will be via inhalation of ambient air and dermal contact(SRC).

Estimated LCt50 /lethal concentration and time/ values for military personnel undergoing vapor exposures ... is ...35 mg-min/cu m for GF.

In studies conducted on rats dosed subcutaneously with agent GB (sarin), agent GD (soman), or GF at 75 ug/kg, ... the major route of elimination for all three agents was urinary excretion.

In studies conducted on rats dosed subcutaneously with agent GB, GD, or GF at 75 ug/kg, ... the major metabolite formed by a nonsaturable mechanism and excreted in the urine was an alkylmethyl phosphonic acid.

The organophosphorus nerve agents are related chemically to organophosphorus insecticides and have a similar mechanism of toxicity, but a much higher mammalian acute toxicity, particularly via the dermal route. Nerve agents phosphonylate a serine hydroxyl group in the active site of the enzyme, acetylcholinesterase (AChE), which results in accumulation of acetylcholine and, in turn, causes enhancement and prolongation of cholinergic effects and depolarization blockade. The rate of spontaneous reactivation of AChE is variable, which partly accounts for differences in acute toxicity between the nerve agents. With soman in particular, an additional reaction occurs known as 'aging'. This consists of monodealkylation of the dialkylphosphonyl enzyme, which is then resistant to spontaneous hydrolysis and reactivation by oximes. Monodealkylation occurs to some extent with all dialkylphosphonylated AChE complexes; however, in general, is only of clinical importance in relation to the treatment of soman poisoning, where it is a very serious problem.

Excerpt from ERG Guide 153 [Substances - Toxic and/or Corrosive (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)

Excerpt from ERG Guide 153 [Substances - Toxic and/or Corrosive (Combustible)]: Ensure that medical personnel are aware of the material(s) involved and take precautions to protect themselves. Move victim to fresh air. Call 911 or emergency medical service. Give artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; give artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim calm and warm. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. (ERG, 2016)

Administration of antidotes is a critical step in managing a nerve agent victim; however, this may be difficult to achieve in the Hot Zone, because the antidotes may not be readily available, and procedures or policies for their administration while in the Hot Zone may be lacking. If the military Mark I kits containing autoinjectors are available, they provide the best way to administer the antidotes. One autoinjector automatically delivers 2 mg atropine and the other automatically delivers 600 mg /pralidoxime chloride/ 2-PAM Cl. /Nerve Agents/|Self-aid: none; soldier will be unable to help himself . Buddy-aid: three MARK I Kits and diazepam immediately. Liquid on Skin. Mild/Moderate: muscle twitching at site of exposure; sweating at site of exposure; nausea, vomiting; feeling of weakness. Time of onset: 10 minutes to 18 hours after exposure. Self-aid: 1-2 MARK I Kits, depending on severity of symptoms. Buddy-aid: stand by. Severe: all of the above, plus breathing difficulty or cessation of breathing; generalized muscular twitching, weakness, or paralysis; convulsions; loss of consciousness; loss of bladder and bowel control. Time of onset: minutes to an hour after exposure. Self-aid: none; soldier will be unable to help himself. Buddy-aid: three MARK I Kits and diazepam immediately. The most important care the casualty receives is the care given within the first several minutes after exposure (self-aid, buddy-aid). Immediate care, including administration of antidotes, can mean the difference between survival and death in a soldier exposed to a nerve agent. It is imperative that every medic/combat lifesaver understand the effects of nerve agents, the time in which effects occur, and the correct steps to take to save the exposed soldier. Every soldier must know the signs and symptoms of mild and severe nerve agent poisoning and the correct first aid in order to evaluate and provide the appropriate self- and buddy-aid. /Nerve agents/|The standard treatment includes AChE reactivators (oximes) in combination with antimuscarinic drugs.|/Experimental antidote:/ Organophosphorus (OP) nerve agents are potent toxins that inhibit cholinesterases and produce a rapid and lethal cholinergic crisis. Development of protein-based therapeutics is being pursued with the goal of preventing nerve agent toxicity and protecting against the long-term side effects of these agents. The drug-metabolizing enzyme human carboxylesterase 1 (hCE1) is a candidate protein-based therapeutic because of its similarity in structure and function to the cholinesterase targets of nerve agent poisoning. However, the ability of wild-type hCE1 to process the G-type nerve agents sarin and cyclosarin has not been determined. We report the crystal structure of hCE1 in complex with the nerve agent cyclosarin. We further use stereoselective nerve agent analogs to establish that hCE1 exhibits a 1700- and 2900-fold preference for the P(R) enantiomers of analogs of soman and cyclosarin, respectively, and a 5-fold preference for the P(S) isomer of a sarin analog. /Investigators/ show that for enzyme inhibited by racemic mixtures of bona fide nerve agents, hCE1 spontaneously reactivates in the presence of sarin but not soman or cyclosarin. The addition of the neutral oxime 2,3-butanedione monoxime increases the rate of reactivation of hCE1 from sarin inhibition by more than 60-fold but has no effect on reactivation with the other agents examined. Taken together, these data demonstrate that hCE1 is only reactivated after inhibition with the more toxic P(S) isomer of sarin. These results provide important insights toward the long-term goal of designing novel forms of hCE1 to act as protein-based therapeutics for nerve agent detoxification.|For more Antidote and Emergency Treatment (Complete) data for CYCLOSARIN (13 total), please visit the HSDB record page.

/SIGNS AND SYMPTOMS/ Children present a clinical picture that can be very different to that observed in adults. Children in cholinergic crisis may not necessarily manifest with miosis (constriction of pupils)... In fact one case series demonstrated absence of myosis in 43% of pediatric victims. Studies involving pediatric exposure to organophosphates /OP/ have suggested the appearance of isolated CNS effects (such as stupor, coma) in the absence of peripheral muscarinic effects. Pediatric victims of OP intoxication display sigmificant muscular weakness and hypotonia in the absence of glandular secretions in 70-100% of cases involving moderate to severe levels of exposure... For adults, a presentation of central intoxication (weakness and hypotonia) from OPs without peripheral muscarinic signs and symptoms would be extremely atypical. /Nerve agents/|/SIGNS AND SYMPTOMS/ The chemical-warfare agents /including cyclosarin/ ... are highly toxic organophosphate ester derivatives of phosphonic acid. They are commonly termed nerve agents as a consequence of their anticholinesterase properties and subsequent adverse effects on smooth and skeletal muscle function as well as the central nervous system. Although the inhibition of cholinesterases within neuroeffector junctions or the effector itself is thought to be responsible for the major toxic effects of nerve agents, these compounds can apparently affect nerve impulse transmission by more direct processes as well|/SIGNS AND SYMPTOMS/ Nerve Agent Effects. Vapor Exposure. Mild: eyes - small pupils (miosis), dim vision; headache; nose - runny nose (rhinorrhea); mouth - salivation; lungs - tightness in the chest; time of onset: seconds to minutes after exposure. Self-aid: 1 MARK I Kit. Buddy-aid: stand by. Severe: all of the above, plus severe breathing difficulty or cessation of respiration; generalized muscular twitching, weakness, or paralysis; convulsions; loss of consciousness; loss of bladder, bowel control. Time of onset: seconds to minutes after exposure. /Nerve agents/|/EPIDEMIOLOGY STUDIES/ More than 100,000 US troops were potentially exposed to chemical warfare agents sarin (GB) and cyclosarin (GF) when an ammunition dump at Khamisiyah, Iraq was destroyed during the 1991 Persian Gulf War (GW). We previously found reduced total gray matter (GM) volume in 40 GW veterans with suspected GB/GF exposure relative to 40 matched, unexposed GW veterans on a 1.5T MR scanner. In this study, /the authors/ reexamine the relationship between GB/GF exposure and volumetric measurements of gross neuroanatomical structures in a different cohort of GW veterans on a 4T MR scanner. Neuropsychological and magnetic resonance imaging (MRI) data from a cross sectional study on Gulf War Illness performed between 2005 and 2010 were used in this study. 4T MRI data were analyzed using automated image processing techniques that produced volumetric measurements of gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF). Binary comparisons of 64 GB/GF exposed veterans and 64 'matched', unexposed veterans revealed reduced GM (p=0.03) and WM (p=0.03) volumes in the exposed veterans. Behaviorally, exposed veterans committed more errors of omission (p=0.02) and tended to have slower responses (p=0.05) than unexposed veterans on the Continuous Performance Test (CPT), a measure sustained and selective attention. Regression analyses confirmed that GB/GF exposure status predicted GM (beta=-0.11, p=0.02) and WM (beta=-0.14, p=0.03) volumes, and number of CPT omission errors (beta=0.22, p=0.02) over and above potentially confounding demographic, clinical, and psychosocial variables. There was no dose-response relationship between estimated levels of GB/GF exposure and brain volume. However, /the authors/ did find an effect of Gulf War Illness/Chronic Multisymptom Illness on both GM and WM volume in the GB/GF exposed veterans. These findings confirm previous reports ...of central nervous system pathology in GW veterans with suspected exposure to low levels of GB/GF two decades after the exposure.|For more Human Toxicity Excerpts (Complete) data for CYCLOSARIN (14 total), please visit the HSDB record page.

CF Me ester

As a group, nerve agents are divided into the G-series agents (G for German, identifying these agents as among those secretly developed by the German Ministry of Defense before and during World War II-they contain a fluorine or cyanide substituent group) and the V agents (which contain a sulfur substituent group). /G-series nerve agents/|Agent GF is currently considered of little strategic interest.|The organophosphate nerve agents tabun (GA), sarin (GB), soman (GD), and cyclosarin (GF) are among the most toxic chemical warfare agents known.

The M256A1 Chemical Agent Detector Kit is a portable chemical agent detector kit that can detect and identify nerve, blister, or blood agents as vapor. It is typically used to determine when it is safe to unmask after a chemical agent attack. A test disk contains a glass ampoule with compounds that react with an agent to give a color change. The ampoule is crushed, the activated test disk is exposed to the ambient air, and the disk is compared to a color chart to determine if an agent is present.|The M18A2 Chemical Agent Detector Kit uses both detector tubes and paper tickets to detect and identify dangerous concentrations of lethal chemicals agents as vapors in the air, as well as liquid chemical agent contamination on exposed surfaces. ... Each kit consists of 12 disposable sampler-detectors, one booklet of M8 paper, and a set of instruction cards ... Each sampler-detector contains a square impregnated spot for blister agents, a circular test spot for blood agents, a star test spot for nerve agents, and a Lewisite-detecting tablet and rubbing tab. There are eight glass ampoules, six containing reagents for testing and two for a chemical heater to vaporize agents at low temperatures. When the ampoules are crushed between the fingers, formed channels in the plastic sheets direct the flow of liquid reagent to wet the test spots. Each test spot or detecting tablet develops a distinctive color that indicated whether a chemical agent is or is not present in the air.|GB and other G-agents react with perhydryl ions at pH 9-10 to form a perphosphonate ion, CH3P(O)(OC3H7)OO-, which has a sufficiently high redox potential to oxidize indole or o-dianisidine to produce colored products. This reaction is thus useful as a method of detection, and <1 mg of GB can be detected in this manner. /G-Agents/|... /A/ useful reagent for detection and estimation of G-agents is diisonitrosoacetone... Coupling agents, such as p-phenylenediamine, increase the reaction rate. /G-Agents/

Organophosphorus nerve agents (OPNAs) continue to pose a threat to military personnel and the general public because of their toxicity and their potential use as weapons of mass destruction. An effective method for the detection of human exposure to OPNAs involves the refluoridation of nerve agents adducted to the serum protein butyrylcholinesterase. The regenerated agents are then enriched by solid-phase extraction and quantified by isotope-dilution gas chromatography-mass spectrometry. /Investigators/ have previously reported improvements that resulted in a 10-fold increase in sensitivity. /Investigators/ have now made further changes to the method that include the addition of confirmation ions, the addition of soman (GD) to the assay, the expansion of the linear range, and the elimination of high-volume injection to decrease background noise and run time while improving sensitivity. This report includes the standard operating procedures for this method for tabun, sarin, soman, cyclohexylsarin, and VX and validation studies. The method's limits of detection ranged from 5.5 to 16.5 pg/mL for the G analogue of VX and GD, respectively. Characterization of quality control (QC) materials resulted in an average coefficient of variation of 15.1% for the five analytes in low QC pools and 11.7% in high QC pools.|Toxic organophosphorus compounds (OPC), e.g., pesticides and nerve agents (NA), are known to phosphylate distinct endogenous proteins in vivo and in vitro. OPC adducts of butyrylcholinesterase and albumin are considered to be valuable biomarkers for retrospective verification of OPC exposure. Therefore, /investigators/ have detected and identified novel adducts of human serum albumin (HSA) by means of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Pure albumin and plasma were incubated with numerous pesticides and NA of the V- and G-type in different molar ratios. Samples were prepared either by sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by in-gel enzymatic cleavage using endoproteinase Glu-C (Glu-C) or by combining highly albumin-selective affinity extraction with ultrafiltration followed by reduction, carbamidomethylation, and enzymatic cleavage (Glu-C) prior to MALDI-TOF MS analysis. Characteristic mass shifts for phosphylation revealed tyrosine adducts at Y(411) (Y(401)KFQNALLVRY(411)TKKVPQVSTPTLVE(425)), Y(148) and Y(150) (I(142)ARRHPY(148)FY(150)APE(153), single and double labeled), and Y(161) (L(154)LFFAKRY(161)KAAFTE(167)) produced by original NA (tabun, sarin, soman, cyclosarin, VX, Chinese VX, and Russian VX) as well as by chlorpyrifos-oxon, diisopropyl fluorophosphate (DFP), paraoxon-ethyl (POE), and profenofos. MALDI-MS/MS of the single-labeled (142)I-E(153) peptide demonstrated that Y(150) was phosphylated with preference to Y(148). Aged albumin adducts were not detected. The procedure described was reproducible and feasible for detection of adducts at the most reactive Y(411)-residue (S/N >or =3) when at least 1% of total albumin was labeled. This was achieved by incubating plasma with molar HSA/OPC ratios ranging from approximately 1:0.03 (all G-type NA, DFP, and POE) to 1:3 (V-type NA, profenofos). Relative signal intensity of the Y(411) adduct correlated well with the spotted relative molar amount underlining the usefulness for quantitative adduct determination. In conclusion, the current analytical design exhibits potential as a verification tool for high-dose exposure.|An analysis method for determining isopropyl methylphosphonic acid (IMPA) and cyclohexyl methylphosphonic acid (CMPA), the metabolic hydrolysis products of toxic organophosphorus nerve agents isopropyl methylphosphonofluoridate (sarin, GB) and cyclohexyl methylphosphonofluoridate (cyclosarin, GF), respectively, has been developed and validated using high-performance liquid chromatography-mass spectrometry with negative ion electrospray ionization with time-of-flight detection (LC-ESI-MS-TOF). The linear range of quantitation was 5 to 125 ng/mL in plasma with a method detection limit of 2 ng/mL for each compound. This method was developed to determine the amount of metabolic hydrolysis that was formed during and after nerve agent exposure in minipigs to account for a major pathway of GB and GF elimination that had not been previously characterized in the bloodstream, particularly during low-level whole-body inhalation experiments. Metabolic hydrolysis accounted for 70% to 90% of the recoverable agent in the bloodstream during exposure, when compared to both unbound and cholinesterase bound agent recovered by fluoride ion reactivation analysis for the same samples. The estimated half-life of IMPA and CMPA in plasma was determined to be 44 and 61 min, respectively. The method utilizes the mass selectivity of LC-ESI-MS-TOF using a bench-top instrument to achieve a detection limit that is consistent with reported LC-MS-MS methods analyzing blood samples.