Accepted Manuscript Novichoks – The A group of organophosphorus chemical warfare agents Marcin Kloske, Zygfryd Witkiewicz PII:
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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
Authors: Marcin KLOSKE, Zygfryd WITKIEWICZ
Institute of Chemistry, Military University of Technology, Warsaw, Poland
*Corresponding author: Zygfryd WITKIEWICZ, Military University of Technology, ul. Gen.
Witolda Urbanowicza 2, 00-908 Warszawa, Poland.
e-mail: [email protected]
Abstract: Novichok use has become symbol for the chemical substances use to carry out
political assassinations. In the last century, poisonous warfare agents were used for the first
time on the battlefields, almost all over the world. After the World War II, new types of
organophosphorus chemical warfare agents were developed. Novichoks are only ones, but the
most important part of them - the 4th generation of chemical warfare agents. Despite the
Chemical Weapons Convention, entered into force in 1997, there is still real threat of use of
chemical weapons. This weapon can be used by both states, and transnational terrorist
organisations. Novichoks, A code-named substances, should be permanently introduced into a
number of chemical substances contained in organophosphorus chemical warfare poisonous
agents. This article presents a short fourth-generation nerve agents’ description. Group A
compounds together with G and V groups compounds are organophosphorus chemical
warfare agents which are very dangerous ones. Our article is an attempt to provide answer for
the question - what are Novichoks? And why they should be introduced into Chemical
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Keywords: Novichok, Chemical weapon, Chemical warfare agents, Nerve agents
Abbreviations: OP – organophosphorus, CWA(s) - chemical warfare agent(s), AChE –
acetylcholinesterase, CWC – Chemical Weapon Convention, WMD - weapon of mass
destruction, NA – nerve agent, CVX – Chinese VX, RVX (VR) - Russian VX, RCA - riot
control agents, OPCW - Organisation for the Prohibition of Chemical Weapons.
32 33 34
ACCEPTED MANUSCRIPT Organophosphorus-based chemical warfare agents (OP CWAs) are the most toxic substances
amongst synthetic chemical ones. Notwithstanding the foregoing, as well as the Chemical
Weapons Convention (CWC) spirit of the law (Witkiewicz et al., 1996), still exists the threat
of the use of chemical warfare is almost growing day by day (Crowley et al., 2018; Guidotti
and Trifirò, 2016; Kenyon et al., 2005; Mangerich and Esser, 2014; Robinson, 2008, 1998;
Rogers, 2014; Simonen, 2017; Stock, 1998; Üzümcü, 2014). CWAs may be used, not only on
the battlefields, during military operations, but still is growing the possibility of its terrorist’s
use. CWAs could be the tool for political opponents’ killings. The threat is still to be expected
(Croddy et al., 2011; Tucker, 2007). In March 2018 an attempt was made to murder Sergei
Skripal with a new poisonous agent called Novichok. In fact, it is a group of chemical
compounds with very high toxicity. The information about these substances is incomplete,
often contradictory. Therefore, this paper describes the available information about this group
of chemical compounds belonging to OP CWAs.
Up to the moment, in literature there is a division of OP CWA(s) into G and V (sub)groups.
These groups are well descripted in the sets of articles and books, as well as are quite well
described in the undisclosed military literature. In this paper we describe G and V group in
general terms, with strict Novichok characterization as one of OP CWA, capable to inhibit
acetylcholinesterase (AChE). Novichoks are described as A-subgroup, without clearly stating
that they are organophosphorus substances with physicochemical and toxic properties similar
to substances belonging to groups G and V. This is probably, due to the fact that there is no
P-C binding in its molecules. However, these substances are organophosphorus compounds
because its molecules contain phosphor and carbon atoms. Therefore, we believe that it is
necessary to introduce the novel OP CWAs division into three subgroups: G, V and A. In this
article we present a justification for this opinion.
Another one very serious problem is the lack of Novichok amongst the chemicals covered by
the CWC schedules. This is still growing political problem, and not may be solved quickly.
Part of this paper is an attempt to deal with this problem.
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Chemical warfare agents general description
Chemical warfare agents are the weapons of mass destruction (WMD) part. Nowadays, WMD
consists of chemical, biological, nuclear and radiological weapons. The chemical warfare
history is probably as old as the humankind. Already in 400 BC, during the Peloponnese War,
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
number was caused by the chemical warfare use during World War I, between 1914 and 1918.
As a result of the poisonous substances use on both sides of the conflict, 85.000 soldiers died,
more than 1.2 million were permanently blinded, burnt and mentally mutilated (Delfino et al.,
2009; Mangerich and Esser, 2014; Ramirez and Bacon, 2004; Sheffy, 2005; Shiver, 1929;
Chemical warfare is referred to, presented together or separately (Ganesan et al., 2010):
1. toxic chemical compounds classified as CWAs or its precursors;
2. munitions and devices especially designed to cause death or other harm, as a CWA release
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.
Chemical munitions may contain ready-made CWAs or its precursors. These precursors, on
the way to the destination area, will react to form CWAs. In the first case the ammunition is
unitary and in the second case binary (Coleman, 2005; Croddy et al., 2002; Ellison, 2000;
Romano, Jr. et al., 2007; Somani and Romano, 2001).
The names and number of categories varies slightly from source to source but in general,
types of chemical warfare agents are as follows (Gupta, 2015):
1. nerve agents, organophosphorus compounds that disrupt the chemical communications
through the nervous system; 2. blister
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methyldichloroarsine, phenyldichloroarsine, lewisite; 3. blood agents - hydrogen cyanide, cyanogen chloride, arsine;
4. pulmonary / choking agents – phosgene, diphosgene, chlorine, chloropicrin;
5. harassing agents, also referred to as Riot Control Agents (RCAs):
1) tear agents – chloroacetophenone,
2) vomiting agents – adamsite, diphenylchloroarsine, diphenylcyanoarsine;
6. incapacitating / psychological agents;
7. toxins - botulinum toxin.
Hitherto, the nerve agents were distinguished into two groups of compounds - G and V. We
are convinced that the current state of knowledge allows us to add the A compounds group,
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
oxidation of P(III) and P(V), they constitute phosphonic or phosphoric esters. They are all the
most lethal of the chemicals produced on the industrial scale and are nerve poisons and
Nerve agents penetrate the body through the respiratory, and gastrointestinal tracts, as well as
through the skin. These compounds do not have smell and taste, and therefore their
penetration into the body is not connected with their penetration consciousness. After a period
of time depending on the absorbed dose, poisoning symptoms emerge. The poisoning gives
symptoms known as muscarinic and nicotinic. The muscarinic effect of poisoning manifests
itself as: narrowing of pupils (myosis) without the possibility of accommodation,
bronchospasm, heart rate release, nausea, vomiting, abdominal pain, diarrhea, incontinence of
urine and faeces, pallor, salivation, sweating, tearing and increased blood pressure. The
nicotinic effect occurs as: tremor and muscle weakness, cramps and paralysis. There are also
effects of central nervous system poisoning: dizziness and severe headache, anxiety, speech
and balance disorders, inhibition of respiratory centre activities, which with paralysis of
respiratory muscles leads to coma and death.
Nerve agents poisoning symptoms are associated with the autonomic nervous system
stimulation by acetylcholine accumulation, which is not decomposed by acetylcholinesterase.
The cholinesterase inhibition is the reason for this.
In addition to their immediate effects, nerve agents also have delayed effects. They take the
form of psychological, neurological and cancer effects. There is also susceptibility to
infectious diseases, liver disorders, pathological changes in blood and bone marrow as well as
Nerve agents have been discovered in Germany before World War II during the development
of organophosphorus pesticides. On an industrial scale, they started to be produced during the
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The OP CWAs G compound group History
In 1936, the OP CWAs, compounds with code names G (G-group) has been discovered in
Germany. On December 23rd this year, during his work on insecticides, Gerhard Schrader
discovered the first chemical compound belonging to the G group. It is nowadays known as
ACCEPTED MANUSCRIPT tabun. After a drop of tabun spilled on the laboratory table, Schrader and his assistant had
myosis, dizziness and shortness of breath. It took them three weeks to recover. The
Wehrmacht had been interested in the discovery and further hidden research was carried out
in a military laboratory. The tabun was initially coded Le 100 and later Trilon 83. In 1938 in
the Schrader's team was discovered compound with code-name T-144 and Trilon-46, known
as sarin. This name is derived from the names of the first developers: Schrader, Ambros,
Ritter and Linde. Sarin has been shown to be about 10 times more toxic than tabun.
Through research on tabun and sarin at the Heidelberg Institute, Kuhn and Henkel received a
soman whose name is derived from the Greek word 'to sleep' or the Latin 'mace'. This
association was marked with the symbol T-300. Cyclosarin was also discovered during the
Second World War.
The tabun test production has been started before the World War II beginning. The test
production process and equipment used in it were complicated. The industrial scale
production during WW II was located in Dyhrenfurth, currently Rokita Chemical Plant in
Brzeg Dolny (Poland). Approximately 3,000 employees were engaged at the plant. Of these,
several hundred were injured and at least several dozen died. About 10,000 to 30,000 tons of
tabun were produced before the plant was taken over by the Soviet army and was probably
moved to Dzerzhinsk, Russia. The slave labour force was employed to take part in tabun
production. One of the inmates was prisoner of the concentration camp at the Dyhrenfurth
plant, professor Andrzej Waksmundzki; in the next years outstanding chemist, analyst and
The OP CWAs discovered in Germany were firstly, in USA called G compounds, with
association to the Germany. These CWAs were named after each other: GA - tabun, GB -
sarin, GD - soman, GE – ethyl sarin, GC - chlorosarin and GF - cyclosarin (Ellison, 2008;
Tucker, 2007). Fig. 1 depicts the G group nerve agents’ chemical structure formulas.
Diisopropylfluorophosphate (DFP) is also included in group G although it was not obtained in
164 165 166
Figure 1 OP CWAs structural formulas for G-group nerve agents: tabun, sarin, soman, ethyl sarin, chlorosarin, cyclosarin, and DFP.
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ACCEPTED MANUSCRIPT In its pure state they are liquids, without colour and odour. Technical purity G group
compounds are coloured. They are characterised by low melting temperatures, and high
boiling temperatures, higher than boiling point of water. Their density is slightly higher than
the density of water. These compounds are well soluble in organic solvents and other OP
CWAs. They are generally poorly soluble in water. Only sarin dissolves in water in all ratios.
The OP CWAs vapours are several times heavier than air. Their persistence in the (battle)field
conditions is up to several hours, and depends on the weather condition. The OP CWAs G-
group degradation products are usually solid substances. They are phosphoric and phosphonic
acid derivatives. Some of them are toxic. The OP CWAs G-group: tabun, sarin, soman
physicochemical properties are summarised in Table 1 and their toxic properties in Table 2.
Table 1 Tabun, sarin, and soman physicochemical properties.
Colourless to brown liquid giving off colourless vapours
Molecular weight Liquid density (g/ml)
167 °C to 200 0C
Vapor pressure mm Hg at 25 C
220 °C to 246 C
Boiling point @ (760 mm Hg) 0
Volatility mg/m @ 25 C
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.
182 183 184
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5 to 35
ICt50 [mg⋅min⋅m ]
LCt502 [mg⋅min⋅m-3] skin
185 186 187
The OP CWAs V compound group
ACCEPTED MANUSCRIPT 189
190 In historical terms, the OP CWAs compound group with code-name V, consists of two
subgroups. The first subgroup consists of choline derivatives and the second subgroup
consists of thiocholine derivatives. Choline derivatives were studied by Tammelin and this
group of compounds is called Tammelin esters. Thiocholine derivatives, called V-gases, are
more important for the military purposes. Fig. 2 shows choline and thiocholine patterns, from
which derivatives containing phosphorus in the molecule were obtained. HO
Figure 2 Choline and thiocholine chemical structures.
In the 1950s in the laboratory of Imperial Chemical Industries Ranajit Ghosh work on
obtaining new organophosphorus pesticides, which are thiocholine derivatives (Gupta, 2015).
One of them was called Amiton, and has been introduced for use in farming. However, it was
quickly turned out, because of the fact, that it was not safe for users and was withdrawn from
use in agriculture. On the contrary, because of its toxicity, it was of interest to military-related
chemists and was studied at the research centre of the British Armed Forces in Porton Down.
Amiton received the codename VG. Amiton has low toxicity compared to other V-gases and
nowadays is not considered as CWA. The sequence of scientific works have resulted in the
synthesis of the OP CWAs group marked with the letter V. According to various sources, this
letter is the first letter of the words (Gupta, 2015; Konopski, 2009): victory, venomous,
virulent or viscous. In the 1950s, research on V-gases was carried out in the USA, Canada and
the Soviet Union, in addition to Great Britain. The best-known V-gas is VX. In addition to
VX, Russian V-gas labelled VR and Chinese CVX are well known.
General time line history of the CWA in the form of milestones are provided in the Table 3.
Table 3 CWA invention milestones.
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CWA agents’ group
Choking, blood and irritant
G group organophosphorus
Examples Chlorine, phosgene, hydrogen cyanide Sulfur mustard, nitrogen mustard, lewisite Tabun, soman, sarin
Relative toxicity dose low
ACCEPTED MANUSCRIPT V group organophosphorus A group organophosphorus
VX, Vx, CVx, VR Novichoks
215 Fig. 3 shows the V-gases, formulas. In addition to these are known other V-gases marked with
symbols: VM, VP, VS, VE.
Figure 3 Chemical structures (from left side): VX, VR, CVX and VG.
From the chemical point of view OP CWAs belonging to their V group, as choline and
thiocholine derivatives, one can distinguish two groups: halides (often fluorides) and alkane
derivatives of phosphoric and phosphonic acid esters. Figure 4 shows the general formula of
224 225 226
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.
Quaternary nitrogen derivatives are solids, well soluble in water, difficult or not soluble in
organic solvents. Quaternary nitrogen-free V-compounds are oily liquids with low water
solubility (1 - 5 %) with a better solubility in organic solvents. In the summertime conditions
in the field they are stable one to three weeks and in the winter are persistent for two up to
three months. Their thermal stability is very good - they decompose at temperatures above
500 K. The V-gases have a low volatility of 10-3 to 10-4 mg/dm3 at 293 K. Therefore, they can
only be used in the aerosol form.
The V-gases hydrolysis half-time is several months. In alkaline conditions hydrolysis is faster
Their destruction is possible with the use of organic chlorine (dichloramines) or alkaline
agents. The physical and chemical properties of several OP CWAs are shown in Table 4.
Table 4 The OP CWAs V-group physicochemical properties.
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Vx Oily liquid that
VX Oily liquid that
CVX No data available
VR Liquid with an
1.0083 < −51 0C because of dissolved impurities; −39 0C calculated 298 (calculated) decomposes
No data available
Boiling point (0C) @ 760 mm Hg
7.29 (air = 1)
No data available
9.2 (air = 1)
No data available
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0.0042 at 20 0C Vapor pressure mm Hg
“oily” consistency which is colourless when pure
@ 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
No data available
No data available
No data available
No data available
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
No data available
No data available
V-compounds are rapidly acting CWAs. Poisoning occurs through the respiratory tract,
mucous membranes and through the skin. Toxic V-agents’ doses are smaller in comparison to
G compounds. Eight hours skin exposure to 10 mg VX leads to death. Table 5 summarises
publicly available the V-gases toxic properties.
Table 5 The V-group OP CWAs toxic properties.
Vx No data available No data available
Properties LD50 (skin) LCt50 (respiratory)
No data available
ICt50 (respiratory) ICt50 (percutaneous)
No data available No data available
10 mg/person (bare skin)
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
The A-group OP CWAs
ACCEPTED MANUSCRIPT 252
253 The A-group of OP CWAs are compounds known as Novichok, although in fact it is a group
that should be defined as Novichoks. They are substances quite well known and noticed
several times in various patents. They are also, at the same time mysterious substances, and
their descriptions in popular articles are often contradictory. The Novichoks public history has
begun with two Russian chemists, who were guided by the idea of environmental protection,
and their concerns regarding the negative impact on the environment of work related to the
production and storage of chemical warfare (Fedorov, 2009a, 2009b).
Novichoks has been discovered in the former Soviet Union as the development work on the
third and fourth generation of chemical warfare agents (Averre, 1995; Kloske, 2018;
Mirzayanov, 2009). These works included inter alia, the construction of binary munitions and
delivery systems. The main research centre for CW was the State Institute for Scientific
Research on Organic Chemistry and Experimental Technologies. Initially, only reconstructive
research was being conducted on the works carried out in western laboratories. At the
beginning of the 1970s, the highest authorities imposed on scientists the development of
poisonous fourth generation substances on their own. These substances had to be:
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
safer than previous generations of CWA during storage and combat use preparation;
d) not mentioned in the lists (also precursors) of Chemical Weapon Convention.
As a result of these assignments, phosphonates and phosphates containing amidine and
guanidine fragments in the molecule - Fig. 5 and formaldehyde oxime - Fig. 6., were
invented. It is also worth mentioning that in the late 20th century, the German company Bayer
developed an organophosphorus pesticide derivative, called Phoxim, whose use in agriculture
was banned in 2007 due to its strong toxic properties - Fig. 7.
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.
283 284 285
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).
Figure 7 Phoxim structural formula.
The programme under which Novichoks were developed was codenamed FOLIANT. The
first public article on Novichok appeared in the weekly Moskovskie Novosti in 1992, on the
eve of Russia ratifying the Chemical Weapons Convention. The authors were two chemists -
Lew Fiodorov and Vil Mirzayanov. According to the authors, the Russian military-chemical
complex was using funds received from the West for the implementation of disarmament
agreements to build a modernised potential for conducting a chemical war. The authors
revealed information allegedly in connection with their concern for the environment. They
were working on measuring the concentration levels of harmful substances in facilities and
outside facilities associated with the chemical weapon programme. These measurements were
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280 281 282
ACCEPTED MANUSCRIPT to prove whether foreign intelligence agencies could detect traces of BST production. The
results of the measurements showed that the levels of toxic agents in the environment were
about eighty times higher than the maximum safe concentrations. For unknown reasons only
one article author - Mirzayanov was arrested and accused of state secrets treason (Konopski,
2009; Mirzayanov, 2009).
The Russian authorities confirmed the existence of Novichoks, indirectly, by treason accusing
of article authors. According to the expert’s testimonies, who were three scientists properly
prepared by the still existing Committee for State Security (KGB); Novichoks and other
chemical substances were indeed produced, and this led directly to the conclusion that the
authors' enunciations were treasonable. Leonid Rink, who claimed to have carried out
doctoral research on Novichoks; indirectly confirmed that the structures described by
Fiodorov and Mirzayanov were correct (Croddy et al., 2011; Gupta, 2015, 2009; Hoenig,
2007). Significantly, Leonid Rink himself was convicted in Russia in 1994 for illegal sale of
this substance, and it was perhaps this sample that made it possible to confirm operationally
the source of the substance used to attack the Skripals.
Only Mirzayanov was arrested on 22 October 1992, and sent to a Lefortovo Prison, probably
for proving that the Russian generals were lying - and are still lying about chemical
disarmament. What is important for the case, and research on ways to protect against
chemical weapons, Mirzayanov currently lives in the USA, where he published an
autobiographical book in 2008 (Mirzayanov, 2009).
In the 1990s, the German Federal Intelligence Service (Bundesnachrichtendienst - BND)
received a Novichok’ sample from a Russian undisclosed scientist, which was then analysed
in Sweden, according to reports from the Reuter agency (“West’s knowledge of Novichok
came from sample secured in 1990s,” 2018). The substance chemical formula and properties
were secretly transferred to selected Western NATO countries, which used it in small
quantities for CBRN equipment testing: protection against contamination, detection,
decontamination and medical means of protection against contamination. Novichok was
mentioned in the patent for the treatment of poisoning with organophosphorus compounds.
Research carried out in this area by the University of Maryland in Baltimore was co-financed
by the US army (Albuquerque et al., 2014).
There is no consensus in the available literature on the naming of the poisonous agents known
as Novichok. Considering that these compounds were to be used in binary ammunition, in
publications the name Novichok is used for individual components (precursors), as well as for
the paralytic and nerve agents themselves. Mostly the term Novichok is used both in
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ACCEPTED MANUSCRIPT nomenclature: paralytic and nerve agents of this group, as well as binary chemical weapons
(the whole system in which the paralytic and convulsive agent is yet to be developed). This is
reflected in the naming of precursors with single digits in their names (e.g. Novichok-5 and
Novichok-7), as well as symbols (e.g. Novichok# and Novichok?). Their reaction products are
referred to by the symbol "A" with a three-digit number (hence the name "A-series
compounds"). Individual authors differ in the use of code names of individual BSTs from the
Novichok group. In 2018 the term "N-series compounds" also appeared. (N-series agents).
Novichok is defined as fourth generation of combat poisonous agents (Croddy et al., 2002;
Gupta, 2015; Hoenig, 2007).
340 The Novichoks synthesis
Possible Novichoks synthesis reaction scheme with code symbols: A-230, A-232, and A-234
were firstly described by Hoenig (Hoenig, 2007). In the first stage of the synthesis reaction, a
cyclic oxime ester is formed, in which the phosphorus atom is five-bound - Fig. 8a. At
temperatures below zero this compound is stable, but during heating the ring with chlorine
transfer is opened, and the corresponding Novichok is formed - Fig 8b.
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348 349 350
Figure 8 Novichoks synthesis scheme according Hoenig.
ACCEPTED MANUSCRIPT The efficiency of this reaction is about 30-60%. According to Hoenig, the structures of
individual Novichoks are as follows (Hoenig, 2007):
Figure 9 Novichoks structures (from left): A-230, A-232, and A-234.
There are described about 50 chemical compounds, which are considered Novichoks
precursors. These are chemical compounds which are poorly soluble in water. They probably
also have toxic properties. Their toxicity is different, generally characteristic for
organophosphorus compounds. The following are examples of chemical compounds that are
precursors of Novichoks - Fig. 10 (Hoenig, 2007; Konopski, 2009):
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TE D ;
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TE D EP
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Figure 10 The formulas of Novichoks precursors.
The first Novichok accepted as a regular CWA in the Soviet army was probably the Novichok
A-230, produced in the Wolsk 12 plant. The same plant also produced Novichok A-232 and
ACCEPTED MANUSCRIPT 397
A-234 as well as their precursors. Properties of these three well-known Novichoks are
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
solidifies at low
does not solidify at low
more volatile than A 230 or RVX
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400 401 402
1.414 g/mL n.a.
less stable against
resistant to moisture
moisture than A 230 or
The compounds mentioned in the table 5, are not suitable for the use as CWAs. The main
reason are their high boiling temperatures and low vapour pressure. Therefore, these chemical
compounds, despite their high toxicity, were not very important as CWAs. According to
Mirzayanow, other industrially produced Novichoks with the numbers 33 and 84, have been
chosen by the Soviet Army. The production of the first of these, in Novocheboxarsk, was to
amount to 15 thousand tonnes (Mirzayanov, 2009).
Nowadays there is no reliable information about Novichoks toxic effects. They are believed to
be several times more toxic than OP CWAs V-group nerve agents. General poisoning
symptoms are similar to another OP CWA. The poisoning mechanism may consist not only in
inhibition of acetylcholinesterase, but also in causing irreversible neuropathy. Therefore, the
treatment of Novichok’s poisoning with antidotes for paralytic and neurotransmitters may be
less effective or ineffective. This may be related to the structural similarity of A-group nerve
agents and oxime compounds used as inhibited acetylcholinesterase reactivators (Cochran et
al., 2011; Moore et al., 1995). Structural similarity between pralidoxime, pyridostigmine, and
novichoks is visible - Fig. 11
Methods of Novichoks analysis are not described in the literature. Taking into account their
molecular structure and mechanism of toxic effects, it can be stated that the methods of their
analysis will be the same as CWA from G and V groups. These will certainly be
chromatographic, enzymatic and phosphorus detection methods in organophosphorus
compounds (Witkiewicz et al., 2018).
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Figure 11 The structure of pralidoxime (a), and pyridostigmine (b).
The OP CWAs A-group compounds (Novichoks) & CWC issues
After the First World War, attempts were made to ban chemical weapons (Croddy et al.,
2002; Gupta, 2015; Witkiewicz et al., 1996). However, these attempts were not effective. It
was not until 1997, before the Chemical Weapon Convention entered into force, which
established the basis for the complete elimination of chemical weapons as a means of warfare.
It imposes a total ban on the manufacture, stockpiling and use of chemical weapons with total
destruction of chemical agents previously produced. The Convention also restricts and
controls international trade in toxic substances and warfare precursors of toxic agents.
The Organisation for the Prohibition of Chemical Weapons (OPCW), based in The Hague,
ensures that the provisions of the Convention are respected. The organs of OPCW are: The
Conference of States Parties, its Executive Council subordinate to it, composed of
representatives of 41 States, in charge of the day-to-day management of the Organisation and
a Technical Secretariat of 500 persons. The Technical Secretariat is the administrative and
technical background of the Conference and the Council and carries out the verification
activities provided for in the Convention using chemical analysis methods (Erickson, 1998;
Mallard, 2014; Newman, 1997; Reddy et al., 2004; Singh et al., 2016; Terzic et al., 2015;
Terzic and de Voogt, 2014; Witkiewicz et al., 2018, 2016). The lists of chemicals covered by
ACCEPTED MANUSCRIPT the CWC are an integral part of the Convention. These lists include all currently known
poisonous chemical warfare agents except Novichoks.
We are aware that the Russians have never disclosed the scope of work on Novichoks or their
possession state, either in bilateral talks with the United States or during CWC preliminary
negotiations. This also applies to Novichok’s precursors. Information published by
Mirzayanov and others has been negated, by the soviet and Russian authorities. 27 September
2017 the OPCW has announced that Russia has destroyed its stockpiles of chemical weapons.
It is not known whether this also applies to Novichoks.
From the authors point of view, it is unreasonable why chemical substances, the existence of
which is beyond doubt - they have certain CAS codes - and which have strong toxic
properties, are not formally listed in the annexes to the CWC. It is also beyond doubt that they
were on chemical weapons of the Red Army.
The lack of Novichoks in the toxic substances CWC lists, could be explained by two reasons.
The first is the fact that Russia has not officially admitted to their production. The second
reason is to be the fear that the inclusion of Novichoks into the CWC Annexes would reveal
their exact chemical structures. This could be used by some countries or terrorist
organisations to produce, and use them. None of these reasons, however, is convincing
because each of them could be used in relation to other CWAs. The existing situation is an
example of the international law standard non-application, by the States that have formally
agreed to abide by this standard in the form of the CWC.
According to some lawyer’s viewpoint the non-inclusion of Novichoks in the CWC lists, does
not prevent them from being covered by the Convention. This is possible on the basis of a
CWC general-purpose criterion. This concept does not appear in the CWC but results from
its content, according to which any toxic substance used for purposes other than those
permitted by the Convention is a chemical weapon. Only to include Novichoks in the
provisions of the CWC expressis verbis would not raise any doubts and is therefore necessary.
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The OP CWAs physicochemical and toxic properties characteristics presented in this review
leads to the conclusion that Novichoks, also known as A-group compounds should not be
treated as an independent group of chemical warfare compounds. When dealing with OP
CWAs, they should be treated in the same way as other nerve agents, distinguishing between
ACCEPTED MANUSCRIPT 479
groups: G, V and A. It is particularly important to include group A compounds in the CWC
lists of toxic agents.
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Albuquerque, E.X., Adler, M., Pereira, E.F.R., 2014. Method of treating organophosphorous poisoning. US8703762B2. Averre, D.L., 1995. The Mirzayanov affair: Russia’s ‘military‐chemical complex.’ Eur. Secur. 4, 273–305. https://doi.org/10.1080/09662839508407219 Cochran, R., Kalisiak, J., Küçükkılınç, T., Radić, Z., Garcia, E., Zhang, L., Ho, K.-Y., Amitai, G., Kovarik, Z., Fokin, V.V., Sharpless, K.B., Taylor, P., 2011. Oxime-assisted Acetylcholinesterase Catalytic Scavengers of Organophosphates That Resist Aging. J. Biol. Chem. 286, 29718–29724. https://doi.org/10.1074/jbc.M111.264739 Coleman, K., 2005. A history of chemical warfare. Palgrave Macmillan, Basingstoke, Hampshire ; New York. Croddy, E., Perez-Armendariz, C., Hart, J., 2011. Chemical and Biological Warfare: A Comprehensive Survey for the Concerned Citizen. Springer New York. Croddy, E., Perez-Armendariz, C., Hart, J., 2002. Chemical and Biological Warfare. Springer New York, New York, NY. https://doi.org/10.1007/978-1-4613-0025-0 Crowley, M., Shang, L., Dando, M., 2018. Preserving the norm against chemical weapons: A civil society initiative for the 2018 4th review conference of the chemical weapons convention. Futures 102, 125–133. https://doi.org/10.1016/j.futures.2018.01.006 Delfino, R.T., Ribeiro, T.S., Figueroa-Villar, J.D., 2009. Organophosphorus compounds as chemical warfare agents: a review. J. Braz. Chem. Soc. 20. https://doi.org/10.1590/S010350532009000300003 Ellison, D.H., 2008. Handbook of chemical and biological warfare agents, 2nd ed. ed. CRC Press, Boca Raton. Ellison, D.H., 2000. Handbook of chemical and biological warfare agents. CRC Press LLC, Boca Raton. Erickson, B., 1998. The Chemical Weapons Convention redefines “analytical challenge.” Anal. Chem. 70, 397A-400A. https://doi.org/10.1021/ac981849p Fedorov, L.A., 2009a. Chimičeskoe vooruženie - vojna s sobstvennym narodom: (tragičeskij rossijskij opyt) 2. 2. Izdat. “Lesnaja Strana,” Moskva. Fedorov, L.A., 2009b. Chimičeskoe vooruženie - vojna s sobstvennym narodom: (tragičeskij rossijskij opyt) 3. 3. Izdat. “Lesnaja Strana,” Moskva. Ganesan, K., Raza, S., Vijayaraghavan, R., 2010. Chemical warfare agents. J. Pharm. Bioallied Sci. 2, 166–178. https://doi.org/10.4103/0975-7406.68498 Guidotti, M., Trifirò, F., 2016. Chemical risk and chemical warfare agents: science and technology against humankind. Toxicol. Environ. Chem. 98, 1018–1025. https://doi.org/10.1080/02772248.2014.996153 Gupta, R.C. (Ed.), 2015. Handbook of toxicology of chemical warfare agents, Second edition. ed. Elsevier/AP, Academic Press is an imprint of Elsevier, Amsterdam ; Boston. Gupta, R.C. (Ed.), 2009. Handbook of toxicology of chemical warfare agents. Elsevier/AP, Amsterdam. Hoenig, S.L., 2007. Compendium of chemical warfare agents. Springer, New York, NY. Kenyon, I.R., Gutschmidt, K., Cosivi, O., 2005. Legal aspects and international assistance related to the deliberate use of chemicals to cause harm. Toxicology 214, 249–255. https://doi.org/10.1016/j.tox.2005.06.017
484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526
M AN U
Kloske, M., 2018. Nowiczok(I) i substancje A. Wiad. Chem. [Z] 72, 723–765. Konopski, L., 2009. Historia broni chemicznej. Bellona, Warszawa. Mallard, W.G., 2014. AMDIS in the Chemical Weapons Convention. Anal. Bioanal. Chem. 406, 5075–5086. https://doi.org/10.1007/s00216-014-7686-y Mangerich, A., Esser, C., 2014. Chemical warfare in the First World War: reflections 100 years later. Arch. Toxicol. 88, 1909–1911. https://doi.org/10.1007/s00204-014-1370-z Mirzayanov, V.S., 2009. State secrets: an insider’s chronicle of the Russian chemical weapons program. Outskirts Press, Inc, Denver, Colorado. Moore, D.H., Clifford, C.B., Crawford, I.T., Cole, G.M., Baggett, J.M., 1995. Review of Nerve Agent Inhibitors and Reactivators of Acetylcholinesterase, in: Quinn, D.M., Balasubramanian, A.S., Doctor, B.P., Taylor, P. (Eds.), Enzymes of the Cholinesterase Family. Springer US, Boston, MA, pp. 297–304. https://doi.org/10.1007/978-1-4899-10516_62 Newman, A., 1997. News from the fall ACS national meeting: Analytical chemistry and the Chemical Weapons Convention. Anal. Chem. 69, 656A-656A. https://doi.org/10.1021/ac9718206 Ramirez, J.G., Bacon, D.R., 2004. Modern Chemical Warfare: A History. Bull. Anesth. Hist. 22, 1–15. https://doi.org/10.1016/S1522-8649(04)50015-X Reddy, T.J., Saradhi, U.V.R.V., Prabhakar, S., Vairamani, M., 2004. Trace level detection and identification of chemicals related to the chemical weapons convention from complex organic samples. J. Chromatogr. A 1038, 225–230. https://doi.org/10.1016/j.chroma.2004.03.028 Robinson, J.P.P., 2008. Difficulties facing the Chemical Weapons Convention. Int. Aff. 84, 223–239. https://doi.org/10.1111/j.1468-2346.2008.00701.x Robinson, J.P.P., 1998. The Impact of Pugwash on the Debates over Chemical and Biological Weapons. Ann. N. Y. Acad. Sci. 866, 224–252. https://doi.org/10.1111/j.17496632.1998.tb09155.x Rogers, P., 2014. A century on the edge: from Cold War to hot world, 1945–2045. Int. Aff. 90, 93–106. https://doi.org/10.1111/1468-2346.12097 Romano, Jr., J., Lukey, B., Salem, H. (Eds.), 2007. Chemical Warfare Agents: Chemistry, Pharmacology, Toxicology, and Therapeutics. CRC Press. https://doi.org/10.1201/9781420046625 Sheffy, Y., 2005. The Chemical Dimension of the Gallipoli Campaign: Introducing Chemical Warfare to the Middle East. War Hist. 12, 278–317. https://doi.org/10.1191/0968344505wh317oa Shiver, H.E., 1929. Chemical warfare: I. History, limitations, and future possibilities. J. Chem. Educ. 6, 2147. https://doi.org/10.1021/ed006p2147 Simonen, K., 2017. Chemical weapons, Ayatollah Khomeini and Islamic law. Glob. Secur. Health Sci. Policy 2, 29–39. https://doi.org/10.1080/23779497.2017.1351308 Singh, V., Purohit, A.K., Chinthakindi, S., Goud, R.D., Tak, V., Pardasani, D., Shrivastava, A.R., Dubey, D.K., 2016. Analysis of chemical warfare agents in organic liquid samples with magnetic dispersive solid phase extraction and gas chromatography mass spectrometry for verification of the chemical weapons convention. J. Chromatogr. A 1448, 32–41. https://doi.org/10.1016/j.chroma.2016.04.058 Somani, S.M., Romano, J.A., 2001. CHEMICAL WARFARE AGENTS: TOXICITY AT LOW LEVELS 441. Stock, T., 1998. Conversion of Chemical Weapons Production Facilities Under the Chemical Weapons Convention, in: Geissler, E., Gazsó, L., Buder, E. (Eds.), Conversion of Former BTW Facilities. Springer Netherlands, Dordrecht, pp. 11–24. https://doi.org/10.1007/978-94011-5306-5_2 Szinicz, L., 2005. History of chemical and biological warfare agents. Toxicology 214, 167–
527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576
M AN U
181. https://doi.org/10.1016/j.tox.2005.06.011 Terzic, O., de Voogt, P., 2014. Modern Sample Preparation Techniques for Gas Chromatography-Mass Spectrometry Analysis of Environmental Markers of Chemical Warfare Agents Use, in: Banoub, J. (Ed.), Detection of Chemical, Biological, Radiological and Nuclear Agents for the Prevention of Terrorism. Springer Netherlands, Dordrecht, pp. 33–67. https://doi.org/10.1007/978-94-017-9238-7_4 Terzic, O., Gregg, H., de Voogt, P., 2015. Identification of chemicals relevant to the Chemical Weapons Convention using the novel sample-preparation methods and strategies of the Mobile Laboratory of the Organization for the Prohibition of Chemical Weapons. TrAC Trends Anal. Chem. 65, 151–166. https://doi.org/10.1016/j.trac.2014.10.012 Tucker, J.B., 2007. War of nerves: chemical warfare from World War I to al-Qaeda, First Anchor Books ed. ed. Anchor Books, New York, NY. Üzümcü, A., 2014. The Chemical Weapons Convention—disarmament, science and technology. Anal. Bioanal. Chem. 406, 5071–5073. https://doi.org/10.1007/s00216-014-79568 West’s knowledge of Novichok came from sample secured in 1990s: report, 2018. . Reuters. Witkiewicz, Z., Jóźwik, R., Starostin, L., 1996. Konwencja o Zakazie Broni Chemicznej. Biul. Wojsk. Akad. Tech. 1996, 5–19. Witkiewicz, Z., Neffe, S., Sliwka, E., Quagliano, J., 2018. Analysis of the Precursors, Simulants and Degradation Products of Chemical Warfare Agents. Crit. Rev. Anal. Chem. 48, 337–371. https://doi.org/10.1080/10408347.2018.1439366 Witkiewicz, Z., Sliwka, E., Neffe, S., 2016. Chromatographic analysis of chemical compounds related to the Chemical Weapons Convention. TrAC Trends Anal. Chem. 85, 21– 33. https://doi.org/10.1016/j.trac.2016.05.006
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ACCEPTED MANUSCRIPT Novichoks – The A group of organophosphorus chemical warfare agents Highlights
1. Novichok is not only a chemical substance, but it is an open collection consisting of at least several dozen substances.
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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