Novichoks – The A group of organophosphorus chemical warfare agents

Novichoks – The A group of organophosphorus chemical warfare agents

Accepted Manuscript Novichoks – The A group of organophosphorus chemical warfare agents Marcin Kloske, Zygfryd Witkiewicz PII: S0045-6535(19)30054-2 ...

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Accepted Manuscript Novichoks – The A group of organophosphorus chemical warfare agents Marcin Kloske, Zygfryd Witkiewicz PII:

S0045-6535(19)30054-2

DOI:

https://doi.org/10.1016/j.chemosphere.2019.01.054

Reference:

CHEM 22969

To appear in:

ECSN

Received Date: 15 November 2018 Revised Date:

4 January 2019

Accepted Date: 7 January 2019

Please cite this article as: Kloske, M., Witkiewicz, Z., Novichoks – The A group of organophosphorus chemical warfare agents, Chemosphere (2019), doi: https://doi.org/10.1016/j.chemosphere.2019.01.054. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Novichoks – The A group of organophosphorus chemical warfare agents

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Authors: Marcin KLOSKE, Zygfryd WITKIEWICZ

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Institute of Chemistry, Military University of Technology, Warsaw, Poland

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*Corresponding author: Zygfryd WITKIEWICZ, Military University of Technology, ul. Gen.

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Witolda Urbanowicza 2, 00-908 Warszawa, Poland.

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e-mail: [email protected]

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Abstract: Novichok use has become symbol for the chemical substances use to carry out

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political assassinations. In the last century, poisonous warfare agents were used for the first

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time on the battlefields, almost all over the world. After the World War II, new types of

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organophosphorus chemical warfare agents were developed. Novichoks are only ones, but the

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most important part of them - the 4th generation of chemical warfare agents. Despite the

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Chemical Weapons Convention, entered into force in 1997, there is still real threat of use of

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chemical weapons. This weapon can be used by both states, and transnational terrorist

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organisations. Novichoks, A code-named substances, should be permanently introduced into a

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number of chemical substances contained in organophosphorus chemical warfare poisonous

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agents. This article presents a short fourth-generation nerve agents’ description. Group A

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compounds together with G and V groups compounds are organophosphorus chemical

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warfare agents which are very dangerous ones. Our article is an attempt to provide answer for

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the question - what are Novichoks? And why they should be introduced into Chemical

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Weapons Convention.

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Keywords: Novichok, Chemical weapon, Chemical warfare agents, Nerve agents

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Abbreviations: OP – organophosphorus, CWA(s) - chemical warfare agent(s), AChE –

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acetylcholinesterase, CWC – Chemical Weapon Convention, WMD - weapon of mass

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destruction, NA – nerve agent, CVX – Chinese VX, RVX (VR) - Russian VX, RCA - riot

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control agents, OPCW - Organisation for the Prohibition of Chemical Weapons.

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1

Introduction

ACCEPTED MANUSCRIPT Organophosphorus-based chemical warfare agents (OP CWAs) are the most toxic substances

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amongst synthetic chemical ones. Notwithstanding the foregoing, as well as the Chemical

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Weapons Convention (CWC) spirit of the law (Witkiewicz et al., 1996), still exists the threat

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of the use of chemical warfare is almost growing day by day (Crowley et al., 2018; Guidotti

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and Trifirò, 2016; Kenyon et al., 2005; Mangerich and Esser, 2014; Robinson, 2008, 1998;

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Rogers, 2014; Simonen, 2017; Stock, 1998; Üzümcü, 2014). CWAs may be used, not only on

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the battlefields, during military operations, but still is growing the possibility of its terrorist’s

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use. CWAs could be the tool for political opponents’ killings. The threat is still to be expected

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(Croddy et al., 2011; Tucker, 2007). In March 2018 an attempt was made to murder Sergei

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Skripal with a new poisonous agent called Novichok. In fact, it is a group of chemical

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compounds with very high toxicity. The information about these substances is incomplete,

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often contradictory. Therefore, this paper describes the available information about this group

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of chemical compounds belonging to OP CWAs.

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Up to the moment, in literature there is a division of OP CWA(s) into G and V (sub)groups.

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These groups are well descripted in the sets of articles and books, as well as are quite well

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described in the undisclosed military literature. In this paper we describe G and V group in

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general terms, with strict Novichok characterization as one of OP CWA, capable to inhibit

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acetylcholinesterase (AChE). Novichoks are described as A-subgroup, without clearly stating

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that they are organophosphorus substances with physicochemical and toxic properties similar

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to substances belonging to groups G and V. This is probably, due to the fact that there is no

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P-C binding in its molecules. However, these substances are organophosphorus compounds

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because its molecules contain phosphor and carbon atoms. Therefore, we believe that it is

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necessary to introduce the novel OP CWAs division into three subgroups: G, V and A. In this

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article we present a justification for this opinion.

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Another one very serious problem is the lack of Novichok amongst the chemicals covered by

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the CWC schedules. This is still growing political problem, and not may be solved quickly.

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Part of this paper is an attempt to deal with this problem.

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Chemical warfare agents general description

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Chemical warfare agents are the weapons of mass destruction (WMD) part. Nowadays, WMD

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consists of chemical, biological, nuclear and radiological weapons. The chemical warfare

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history is probably as old as the humankind. Already in 400 BC, during the Peloponnese War,

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the Sparta army used sulphur vapours against the Athens army. Later, chemical substances 2

ACCEPTED MANUSCRIPT were used many times and in various forms during military operations. The highest victim

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number was caused by the chemical warfare use during World War I, between 1914 and 1918.

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As a result of the poisonous substances use on both sides of the conflict, 85.000 soldiers died,

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more than 1.2 million were permanently blinded, burnt and mentally mutilated (Delfino et al.,

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2009; Mangerich and Esser, 2014; Ramirez and Bacon, 2004; Sheffy, 2005; Shiver, 1929;

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Szinicz, 2005).

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Chemical warfare is referred to, presented together or separately (Ganesan et al., 2010):

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1. toxic chemical compounds classified as CWAs or its precursors;

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2. munitions and devices especially designed to cause death or other harm, as a CWA release

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result;

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3. any additional equipment intentionally designed for use in direct abovementioned CWAs release conjunction.

Chemical warfare may be considered to be CWAs, and delivery means to the destination area.

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Chemical munitions may contain ready-made CWAs or its precursors. These precursors, on

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the way to the destination area, will react to form CWAs. In the first case the ammunition is

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unitary and in the second case binary (Coleman, 2005; Croddy et al., 2002; Ellison, 2000;

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Romano, Jr. et al., 2007; Somani and Romano, 2001).

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The names and number of categories varies slightly from source to source but in general,

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types of chemical warfare agents are as follows (Gupta, 2015):

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1. nerve agents, organophosphorus compounds that disrupt the chemical communications

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through the nervous system; 2. blister

agents



sulphur

mustard,

nitrogen

mustard,

ethyldichloroarsine,

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methyldichloroarsine, phenyldichloroarsine, lewisite; 3. blood agents - hydrogen cyanide, cyanogen chloride, arsine;

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4. pulmonary / choking agents – phosgene, diphosgene, chlorine, chloropicrin;

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5. harassing agents, also referred to as Riot Control Agents (RCAs):

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1) tear agents – chloroacetophenone,

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2) vomiting agents – adamsite, diphenylchloroarsine, diphenylcyanoarsine;

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3) malodorants;

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6. incapacitating / psychological agents;

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7. toxins - botulinum toxin.

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Hitherto, the nerve agents were distinguished into two groups of compounds - G and V. We

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are convinced that the current state of knowledge allows us to add the A compounds group,

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e.g. Novichok, to nerve agent’s group family. In the molecules of these compounds, there is 3

ACCEPTED MANUSCRIPT phosphorus and an organic fragment - containing carbon. Depending on the degree of

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oxidation of P(III) and P(V), they constitute phosphonic or phosphoric esters. They are all the

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most lethal of the chemicals produced on the industrial scale and are nerve poisons and

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neurotoxins.

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Nerve agents penetrate the body through the respiratory, and gastrointestinal tracts, as well as

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through the skin. These compounds do not have smell and taste, and therefore their

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penetration into the body is not connected with their penetration consciousness. After a period

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of time depending on the absorbed dose, poisoning symptoms emerge. The poisoning gives

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symptoms known as muscarinic and nicotinic. The muscarinic effect of poisoning manifests

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itself as: narrowing of pupils (myosis) without the possibility of accommodation,

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bronchospasm, heart rate release, nausea, vomiting, abdominal pain, diarrhea, incontinence of

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urine and faeces, pallor, salivation, sweating, tearing and increased blood pressure. The

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nicotinic effect occurs as: tremor and muscle weakness, cramps and paralysis. There are also

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effects of central nervous system poisoning: dizziness and severe headache, anxiety, speech

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and balance disorders, inhibition of respiratory centre activities, which with paralysis of

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respiratory muscles leads to coma and death.

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Nerve agents poisoning symptoms are associated with the autonomic nervous system

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stimulation by acetylcholine accumulation, which is not decomposed by acetylcholinesterase.

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The cholinesterase inhibition is the reason for this.

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In addition to their immediate effects, nerve agents also have delayed effects. They take the

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form of psychological, neurological and cancer effects. There is also susceptibility to

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infectious diseases, liver disorders, pathological changes in blood and bone marrow as well as

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eye damage.

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Nerve agents have been discovered in Germany before World War II during the development

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of organophosphorus pesticides. On an industrial scale, they started to be produced during the

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War.

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3.1

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The OP CWAs G compound group History

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In 1936, the OP CWAs, compounds with code names G (G-group) has been discovered in

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Germany. On December 23rd this year, during his work on insecticides, Gerhard Schrader

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discovered the first chemical compound belonging to the G group. It is nowadays known as

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ACCEPTED MANUSCRIPT tabun. After a drop of tabun spilled on the laboratory table, Schrader and his assistant had

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myosis, dizziness and shortness of breath. It took them three weeks to recover. The

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Wehrmacht had been interested in the discovery and further hidden research was carried out

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in a military laboratory. The tabun was initially coded Le 100 and later Trilon 83. In 1938 in

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the Schrader's team was discovered compound with code-name T-144 and Trilon-46, known

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as sarin. This name is derived from the names of the first developers: Schrader, Ambros,

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Ritter and Linde. Sarin has been shown to be about 10 times more toxic than tabun.

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Through research on tabun and sarin at the Heidelberg Institute, Kuhn and Henkel received a

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soman whose name is derived from the Greek word 'to sleep' or the Latin 'mace'. This

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association was marked with the symbol T-300. Cyclosarin was also discovered during the

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Second World War.

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The tabun test production has been started before the World War II beginning. The test

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production process and equipment used in it were complicated. The industrial scale

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production during WW II was located in Dyhrenfurth, currently Rokita Chemical Plant in

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Brzeg Dolny (Poland). Approximately 3,000 employees were engaged at the plant. Of these,

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several hundred were injured and at least several dozen died. About 10,000 to 30,000 tons of

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tabun were produced before the plant was taken over by the Soviet army and was probably

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moved to Dzerzhinsk, Russia. The slave labour force was employed to take part in tabun

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production. One of the inmates was prisoner of the concentration camp at the Dyhrenfurth

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plant, professor Andrzej Waksmundzki; in the next years outstanding chemist, analyst and

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chromatographer.

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The OP CWAs discovered in Germany were firstly, in USA called G compounds, with

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association to the Germany. These CWAs were named after each other: GA - tabun, GB -

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sarin, GD - soman, GE – ethyl sarin, GC - chlorosarin and GF - cyclosarin (Ellison, 2008;

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Tucker, 2007). Fig. 1 depicts the G group nerve agents’ chemical structure formulas.

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Diisopropylfluorophosphate (DFP) is also included in group G although it was not obtained in

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Germany.

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Figure 1 OP CWAs structural formulas for G-group nerve agents: tabun, sarin, soman, ethyl sarin, chlorosarin, cyclosarin, and DFP.

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3.2

Properties

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ACCEPTED MANUSCRIPT In its pure state they are liquids, without colour and odour. Technical purity G group

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compounds are coloured. They are characterised by low melting temperatures, and high

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boiling temperatures, higher than boiling point of water. Their density is slightly higher than

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the density of water. These compounds are well soluble in organic solvents and other OP

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CWAs. They are generally poorly soluble in water. Only sarin dissolves in water in all ratios.

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The OP CWAs vapours are several times heavier than air. Their persistence in the (battle)field

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conditions is up to several hours, and depends on the weather condition. The OP CWAs G-

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group degradation products are usually solid substances. They are phosphoric and phosphonic

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acid derivatives. Some of them are toxic. The OP CWAs G-group: tabun, sarin, soman

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physicochemical properties are summarised in Table 1 and their toxic properties in Table 2.

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Table 1 Tabun, sarin, and soman physicochemical properties.

Tabun

Appearance

Soman

Colourless to brown liquid giving off colourless vapours

Molecular formula

C5H11N2O2P 162.12

Molecular weight Liquid density (g/ml)

C4H10FO2P 140.10

1.07

Freezing point(0C)

-50

182.20

1.09

1.02

-57

-42

158 C

167 °C to 200 0C

5.63

4.86

6.33

Vapor pressure mm Hg at 25 C

0.07

2.90

0.40

3

61.0

22.0

3.90

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Vapor density

0

C7Hl6P02F

220 °C to 246 C

Boiling point @ (760 mm Hg) 0

0

Volatility mg/m @ 25 C

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Table 2 Tabun, sarin, and soman toxic properties. Notes: 1 - average incapacitant dose if it is passed through: skin / respiratory system; 2 - average lethal dose if it is passed through skin / respiratory system.

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Sarin

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Properties

Properties 1

Tabun

Sarin

skin

no data

no data

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respiratory system

5 to 35

200

35

-3

Soman

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ICt50 [mg⋅min⋅m ]

LCt502 [mg⋅min⋅m-3] skin

1000

40 000

100

respiratory system

100

300

50

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The OP CWAs V compound group

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4.1

History

190 In historical terms, the OP CWAs compound group with code-name V, consists of two

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subgroups. The first subgroup consists of choline derivatives and the second subgroup

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consists of thiocholine derivatives. Choline derivatives were studied by Tammelin and this

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group of compounds is called Tammelin esters. Thiocholine derivatives, called V-gases, are

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more important for the military purposes. Fig. 2 shows choline and thiocholine patterns, from

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which derivatives containing phosphorus in the molecule were obtained. HO

HS N+

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N+

Figure 2 Choline and thiocholine chemical structures.

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In the 1950s in the laboratory of Imperial Chemical Industries Ranajit Ghosh work on

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obtaining new organophosphorus pesticides, which are thiocholine derivatives (Gupta, 2015).

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One of them was called Amiton, and has been introduced for use in farming. However, it was

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quickly turned out, because of the fact, that it was not safe for users and was withdrawn from

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use in agriculture. On the contrary, because of its toxicity, it was of interest to military-related

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chemists and was studied at the research centre of the British Armed Forces in Porton Down.

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Amiton received the codename VG. Amiton has low toxicity compared to other V-gases and

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nowadays is not considered as CWA. The sequence of scientific works have resulted in the

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synthesis of the OP CWAs group marked with the letter V. According to various sources, this

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letter is the first letter of the words (Gupta, 2015; Konopski, 2009): victory, venomous,

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virulent or viscous. In the 1950s, research on V-gases was carried out in the USA, Canada and

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the Soviet Union, in addition to Great Britain. The best-known V-gas is VX. In addition to

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VX, Russian V-gas labelled VR and Chinese CVX are well known.

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General time line history of the CWA in the form of milestones are provided in the Table 3.

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Table 3 CWA invention milestones.

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Year

CWA agents’ group

1914

Choking, blood and irritant

1917

Blister

1936

Nerve agents

G group organophosphorus

Examples Chlorine, phosgene, hydrogen cyanide Sulfur mustard, nitrogen mustard, lewisite Tabun, soman, sarin

Relative toxicity dose low

high





high

low

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ACCEPTED MANUSCRIPT V group organophosphorus A group organophosphorus

~1950 ~1970

VX, Vx, CVx, VR Novichoks

215 Fig. 3 shows the V-gases, formulas. In addition to these are known other V-gases marked with

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symbols: VM, VP, VS, VE.

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O

O

S N

O

S

P

N

O

S

P

N

P

N

P

S

O

O

O

O

O

Figure 3 Chemical structures (from left side): VX, VR, CVX and VG.

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From the chemical point of view OP CWAs belonging to their V group, as choline and

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thiocholine derivatives, one can distinguish two groups: halides (often fluorides) and alkane

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derivatives of phosphoric and phosphonic acid esters. Figure 4 shows the general formula of

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V compounds.

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Figure 4 General OP CWAs chemical structure formula for the V-gases; X: -OR, -R, -NH2; Y: -OH, halogen (pseudo halogen); Z: -NR2, N+R3.

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4.2

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Quaternary nitrogen derivatives are solids, well soluble in water, difficult or not soluble in

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organic solvents. Quaternary nitrogen-free V-compounds are oily liquids with low water

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solubility (1 - 5 %) with a better solubility in organic solvents. In the summertime conditions

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in the field they are stable one to three weeks and in the winter are persistent for two up to

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three months. Their thermal stability is very good - they decompose at temperatures above

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500 K. The V-gases have a low volatility of 10-3 to 10-4 mg/dm3 at 293 K. Therefore, they can

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only be used in the aerosol form.

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The V-gases hydrolysis half-time is several months. In alkaline conditions hydrolysis is faster

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Their destruction is possible with the use of organic chlorine (dichloramines) or alkaline

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agents. The physical and chemical properties of several OP CWAs are shown in Table 4.

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Table 4 The OP CWAs V-group physicochemical properties.

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V-gases properties

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Properties Appearance

Vx Oily liquid that

VX Oily liquid that

CVX No data available

VR Liquid with an

VG Colourless

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ACCEPTED MANUSCRIPT

1.062

1.0083 < −51 0C because of dissolved impurities; −39 0C calculated 298 (calculated) decomposes

Melting point(0C)

No data available

Boiling point (0C) @ 760 mm Hg

256 (calculated)

Vapor density

7.29 (air = 1)

liquid

C11H26NO2PS 267.37

C11H26NO2PS 267.38

C10H24NO3PS 269.3

1.0

1.003

1.048

No data available

328.3±44.0

9.2 (air = 1)

No data available

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0.0042 at 20 0C Vapor pressure mm Hg

Volatility mg/m3

“oily” consistency which is colourless when pure

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@ 25 0C

is clear, and tasteless. It is amber coloured similar in appearance to motor oil C11H26NO2PS 267.37

0.0066 at 25 0C 48 at 20 0C 75 mg/m3 at 25 0C

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No data available

No data available

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No data available

No data available

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Molecular formula Molecular weight Liquid density (gm/ml)

is clear, and tasteless. It is amber coloured similar in appearance to motor oil C7H18NO2PS 211.2

0.0007 at 25 0C

0.0±0.7 at 25 0C

0.00026 at 25 0C

0.00054 at 25 0C

10.5

No data available

8.9 mg/m3

No data available

V-compounds are rapidly acting CWAs. Poisoning occurs through the respiratory tract,

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mucous membranes and through the skin. Toxic V-agents’ doses are smaller in comparison to

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G compounds. Eight hours skin exposure to 10 mg VX leads to death. Table 5 summarises

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publicly available the V-gases toxic properties.

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Table 5 The V-group OP CWAs toxic properties.

Vx No data available No data available

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Properties LD50 (skin) LCt50 (respiratory)

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LCt50 (percutaneous)

No data available

ICt50 (respiratory) ICt50 (percutaneous)

No data available No data available

VX

VR

10 mg/person (bare skin)

11.3 µg/kg

30 mg⋅min⋅m-3 (mild activity)

No data available

100 mg⋅min⋅m-3 (resting) 6 ÷ 360 mg⋅min⋅m-3 (bare skin) 6 ÷ 3,600 mg⋅min⋅m-3 (clothed)

No data available

24 mg⋅min⋅m-3 (mild activity) 50 mg⋅min⋅m-3 (resting)

No data available No data available

VG No data available No data available No data available No data available No data available

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5

The A-group OP CWAs

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5.1

History

253 The A-group of OP CWAs are compounds known as Novichok, although in fact it is a group

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that should be defined as Novichoks. They are substances quite well known and noticed

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several times in various patents. They are also, at the same time mysterious substances, and

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their descriptions in popular articles are often contradictory. The Novichoks public history has

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begun with two Russian chemists, who were guided by the idea of environmental protection,

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and their concerns regarding the negative impact on the environment of work related to the

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production and storage of chemical warfare (Fedorov, 2009a, 2009b).

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Novichoks has been discovered in the former Soviet Union as the development work on the

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third and fourth generation of chemical warfare agents (Averre, 1995; Kloske, 2018;

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Mirzayanov, 2009). These works included inter alia, the construction of binary munitions and

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delivery systems. The main research centre for CW was the State Institute for Scientific

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Research on Organic Chemistry and Experimental Technologies. Initially, only reconstructive

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research was being conducted on the works carried out in western laboratories. At the

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beginning of the 1970s, the highest authorities imposed on scientists the development of

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poisonous fourth generation substances on their own. These substances had to be:

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a)

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undetectable using standard chemical detection instruments fitted to the NATO member

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states armies in the 1970s and 1980s;

b) able to penetrate the enemy soldier's body despite the application of individual protection

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measures; c)

safer than previous generations of CWA during storage and combat use preparation;

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d) not mentioned in the lists (also precursors) of Chemical Weapon Convention.

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As a result of these assignments, phosphonates and phosphates containing amidine and

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guanidine fragments in the molecule - Fig. 5 and formaldehyde oxime - Fig. 6., were

277

invented. It is also worth mentioning that in the late 20th century, the German company Bayer

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developed an organophosphorus pesticide derivative, called Phoxim, whose use in agriculture

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was banned in 2007 due to its strong toxic properties - Fig. 7.

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Figure 5 General OP CWAs chemical structures for amidine & guanidine X = F or S-alkyl; R1 = O-alkyl (phosphate derivative) or alkyl (phosphonate derivative); R2, R3, R4, R5 = H, alkyl, phenyl, -CN.

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Figure 6 General organophosphorus derivatives of formaldehyde oxime formula; X1 = F; X2 = any halogen, CF2NO2, CN; X3 = any halogen, CN, R = O-alkyl (phosphate derivative) or alkyl (phosphonate derivative).

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Figure 7 Phoxim structural formula.

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The programme under which Novichoks were developed was codenamed FOLIANT. The

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first public article on Novichok appeared in the weekly Moskovskie Novosti in 1992, on the

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eve of Russia ratifying the Chemical Weapons Convention. The authors were two chemists -

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Lew Fiodorov and Vil Mirzayanov. According to the authors, the Russian military-chemical

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complex was using funds received from the West for the implementation of disarmament

293

agreements to build a modernised potential for conducting a chemical war. The authors

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revealed information allegedly in connection with their concern for the environment. They

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were working on measuring the concentration levels of harmful substances in facilities and

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outside facilities associated with the chemical weapon programme. These measurements were

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ACCEPTED MANUSCRIPT to prove whether foreign intelligence agencies could detect traces of BST production. The

298

results of the measurements showed that the levels of toxic agents in the environment were

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about eighty times higher than the maximum safe concentrations. For unknown reasons only

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one article author - Mirzayanov was arrested and accused of state secrets treason (Konopski,

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2009; Mirzayanov, 2009).

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The Russian authorities confirmed the existence of Novichoks, indirectly, by treason accusing

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of article authors. According to the expert’s testimonies, who were three scientists properly

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prepared by the still existing Committee for State Security (KGB); Novichoks and other

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chemical substances were indeed produced, and this led directly to the conclusion that the

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authors' enunciations were treasonable. Leonid Rink, who claimed to have carried out

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doctoral research on Novichoks; indirectly confirmed that the structures described by

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Fiodorov and Mirzayanov were correct (Croddy et al., 2011; Gupta, 2015, 2009; Hoenig,

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2007). Significantly, Leonid Rink himself was convicted in Russia in 1994 for illegal sale of

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this substance, and it was perhaps this sample that made it possible to confirm operationally

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the source of the substance used to attack the Skripals.

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Only Mirzayanov was arrested on 22 October 1992, and sent to a Lefortovo Prison, probably

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for proving that the Russian generals were lying - and are still lying about chemical

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disarmament. What is important for the case, and research on ways to protect against

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chemical weapons, Mirzayanov currently lives in the USA, where he published an

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autobiographical book in 2008 (Mirzayanov, 2009).

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In the 1990s, the German Federal Intelligence Service (Bundesnachrichtendienst - BND)

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received a Novichok’ sample from a Russian undisclosed scientist, which was then analysed

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in Sweden, according to reports from the Reuter agency (“West’s knowledge of Novichok

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came from sample secured in 1990s,” 2018). The substance chemical formula and properties

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were secretly transferred to selected Western NATO countries, which used it in small

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quantities for CBRN equipment testing: protection against contamination, detection,

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decontamination and medical means of protection against contamination. Novichok was

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mentioned in the patent for the treatment of poisoning with organophosphorus compounds.

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Research carried out in this area by the University of Maryland in Baltimore was co-financed

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by the US army (Albuquerque et al., 2014).

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There is no consensus in the available literature on the naming of the poisonous agents known

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as Novichok. Considering that these compounds were to be used in binary ammunition, in

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publications the name Novichok is used for individual components (precursors), as well as for

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the paralytic and nerve agents themselves. Mostly the term Novichok is used both in

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(the whole system in which the paralytic and convulsive agent is yet to be developed). This is

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reflected in the naming of precursors with single digits in their names (e.g. Novichok-5 and

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Novichok-7), as well as symbols (e.g. Novichok# and Novichok?). Their reaction products are

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referred to by the symbol "A" with a three-digit number (hence the name "A-series

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compounds"). Individual authors differ in the use of code names of individual BSTs from the

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Novichok group. In 2018 the term "N-series compounds" also appeared. (N-series agents).

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Novichok is defined as fourth generation of combat poisonous agents (Croddy et al., 2002;

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Gupta, 2015; Hoenig, 2007).

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340 The Novichoks synthesis

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Possible Novichoks synthesis reaction scheme with code symbols: A-230, A-232, and A-234

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were firstly described by Hoenig (Hoenig, 2007). In the first stage of the synthesis reaction, a

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cyclic oxime ester is formed, in which the phosphorus atom is five-bound - Fig. 8a. At

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temperatures below zero this compound is stable, but during heating the ring with chlorine

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transfer is opened, and the corresponding Novichok is formed - Fig 8b.

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Figure 8 Novichoks synthesis scheme according Hoenig.

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ACCEPTED MANUSCRIPT The efficiency of this reaction is about 30-60%. According to Hoenig, the structures of

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individual Novichoks are as follows (Hoenig, 2007):

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Figure 9 Novichoks structures (from left): A-230, A-232, and A-234.

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There are described about 50 chemical compounds, which are considered Novichoks

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precursors. These are chemical compounds which are poorly soluble in water. They probably

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also have toxic properties. Their toxicity is different, generally characteristic for

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organophosphorus compounds. The following are examples of chemical compounds that are

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precursors of Novichoks - Fig. 10 (Hoenig, 2007; Konopski, 2009):

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Figure 10 The formulas of Novichoks precursors.

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5.3

Novichoks properties

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The first Novichok accepted as a regular CWA in the Soviet army was probably the Novichok

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A-230, produced in the Wolsk 12 plant. The same plant also produced Novichok A-232 and

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A-234 as well as their precursors. Properties of these three well-known Novichoks are

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presented in the Table 6:

399 Table 6 The codename A-agents open access physical and chemical properties (n.a. data not available). Source: Chemical warfare agent NOVICHOK - mini-review of available data Article in Food and Chemical Toxicology 121 · September 2018 with 54 Reads DOI: 10.1016/j.fct.2018.09.015

A 230

A 232

A 234

Molecular mass

241.95

255.97

Boiling point

61–62 °C

70–71 °C

Density

1.612 g/mL

1.515 g/mL

State

liquid

n.a.

Low temperature

solidifies at low

does not solidify at low

behaviour

temperature

temperature

Volatility

volatile

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more volatile than A 230 or RVX

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n.a.

less stable against

Moisture stability

resistant to moisture

moisture than A 230 or

n.a.

RVX

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The compounds mentioned in the table 5, are not suitable for the use as CWAs. The main

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reason are their high boiling temperatures and low vapour pressure. Therefore, these chemical

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compounds, despite their high toxicity, were not very important as CWAs. According to

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Mirzayanow, other industrially produced Novichoks with the numbers 33 and 84, have been

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chosen by the Soviet Army. The production of the first of these, in Novocheboxarsk, was to

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amount to 15 thousand tonnes (Mirzayanov, 2009).

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Nowadays there is no reliable information about Novichoks toxic effects. They are believed to

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be several times more toxic than OP CWAs V-group nerve agents. General poisoning

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symptoms are similar to another OP CWA. The poisoning mechanism may consist not only in

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inhibition of acetylcholinesterase, but also in causing irreversible neuropathy. Therefore, the

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treatment of Novichok’s poisoning with antidotes for paralytic and neurotransmitters may be

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less effective or ineffective. This may be related to the structural similarity of A-group nerve

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agents and oxime compounds used as inhibited acetylcholinesterase reactivators (Cochran et

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al., 2011; Moore et al., 1995). Structural similarity between pralidoxime, pyridostigmine, and

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novichoks is visible - Fig. 11

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b

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Methods of Novichoks analysis are not described in the literature. Taking into account their

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molecular structure and mechanism of toxic effects, it can be stated that the methods of their

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analysis will be the same as CWA from G and V groups. These will certainly be

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chromatographic, enzymatic and phosphorus detection methods in organophosphorus

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compounds (Witkiewicz et al., 2018).

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Figure 11 The structure of pralidoxime (a), and pyridostigmine (b).

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The OP CWAs A-group compounds (Novichoks) & CWC issues

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After the First World War, attempts were made to ban chemical weapons (Croddy et al.,

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2002; Gupta, 2015; Witkiewicz et al., 1996). However, these attempts were not effective. It

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was not until 1997, before the Chemical Weapon Convention entered into force, which

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established the basis for the complete elimination of chemical weapons as a means of warfare.

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It imposes a total ban on the manufacture, stockpiling and use of chemical weapons with total

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destruction of chemical agents previously produced. The Convention also restricts and

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controls international trade in toxic substances and warfare precursors of toxic agents.

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The Organisation for the Prohibition of Chemical Weapons (OPCW), based in The Hague,

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ensures that the provisions of the Convention are respected. The organs of OPCW are: The

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Conference of States Parties, its Executive Council subordinate to it, composed of

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representatives of 41 States, in charge of the day-to-day management of the Organisation and

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a Technical Secretariat of 500 persons. The Technical Secretariat is the administrative and

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technical background of the Conference and the Council and carries out the verification

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activities provided for in the Convention using chemical analysis methods (Erickson, 1998;

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Mallard, 2014; Newman, 1997; Reddy et al., 2004; Singh et al., 2016; Terzic et al., 2015;

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Terzic and de Voogt, 2014; Witkiewicz et al., 2018, 2016). The lists of chemicals covered by

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poisonous chemical warfare agents except Novichoks.

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We are aware that the Russians have never disclosed the scope of work on Novichoks or their

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possession state, either in bilateral talks with the United States or during CWC preliminary

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negotiations. This also applies to Novichok’s precursors. Information published by

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Mirzayanov and others has been negated, by the soviet and Russian authorities. 27 September

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2017 the OPCW has announced that Russia has destroyed its stockpiles of chemical weapons.

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It is not known whether this also applies to Novichoks.

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From the authors point of view, it is unreasonable why chemical substances, the existence of

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which is beyond doubt - they have certain CAS codes - and which have strong toxic

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properties, are not formally listed in the annexes to the CWC. It is also beyond doubt that they

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were on chemical weapons of the Red Army.

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The lack of Novichoks in the toxic substances CWC lists, could be explained by two reasons.

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The first is the fact that Russia has not officially admitted to their production. The second

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reason is to be the fear that the inclusion of Novichoks into the CWC Annexes would reveal

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their exact chemical structures. This could be used by some countries or terrorist

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organisations to produce, and use them. None of these reasons, however, is convincing

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because each of them could be used in relation to other CWAs. The existing situation is an

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example of the international law standard non-application, by the States that have formally

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agreed to abide by this standard in the form of the CWC.

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According to some lawyer’s viewpoint the non-inclusion of Novichoks in the CWC lists, does

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not prevent them from being covered by the Convention. This is possible on the basis of a

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CWC general-purpose criterion. This concept does not appear in the CWC but results from

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its content, according to which any toxic substance used for purposes other than those

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permitted by the Convention is a chemical weapon. Only to include Novichoks in the

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provisions of the CWC expressis verbis would not raise any doubts and is therefore necessary.

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Conclusion

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The OP CWAs physicochemical and toxic properties characteristics presented in this review

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leads to the conclusion that Novichoks, also known as A-group compounds should not be

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treated as an independent group of chemical warfare compounds. When dealing with OP

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CWAs, they should be treated in the same way as other nerve agents, distinguishing between

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groups: G, V and A. It is particularly important to include group A compounds in the CWC

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lists of toxic agents.

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1. Novichok is not only a chemical substance, but it is an open collection consisting of at least several dozen substances.

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2. Novichoks are chemical warfare agents not included in the formalised Chemical Weapons Convention schedules.

3. Novichoks are subsequent to G and V compounds, organophosphorus chemical warfare

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agents (sub)group.