Skip to content
Publicly Available Published by De Gruyter September 19, 2018

Advice from the Scientific Advisory Board of the Organisation for the Prohibition of Chemical Weapons on isotopically labelled chemicals and stereoisomers in relation to the Chemical Weapons Convention

  • Christopher M. Timperley EMAIL logo , Jonathan E. Forman EMAIL logo , Mohammad Abdollahi , Abdullah Saeed Al-Amri , Isel Pascual Alonso , Augustin Baulig , Veronica Borrett , Flerida A. Cariño , Christophe Curty , David Gonzalez , Zrinka Kovarik , Roberto Martínez-Álvarez , Robert Mikulak , Nicia Maria Fusaro Mourão , Ponnadurai Ramasami , Slawomir Neffe , Syed K. Raza , Valentin Rubaylo , Koji Takeuchi , Cheng Tang , Ferruccio Trifirò , Francois Mauritz van Straten , Paula S. Vanninen , Volodymyr Zaitsev , Farhat Waqar , Mongia Saïd Zina , Stian Holen and Hope A. Weinstein

Abstract

The Chemical Weapons Convention (CWC) is an international disarmament treaty that prohibits the development, stockpiling and use of chemical weapons. This treaty has 193 States Parties (nations for which the treaty is binding) and entered into force in 1997. The CWC contains schedules of chemicals that have been associated with chemical warfare programmes. These scheduled chemicals must be declared by the States that possess them and are subject to verification by the Organisation for the Prohibition of Chemical Weapons (OPCW, the implementing body of the CWC). Isotopically labelled and stereoisomeric variants of the scheduled chemicals have presented ambiguities for interpretation of the requirements of treaty implementation, and advice was sought from the OPCW’s Scientific Advisory Board (SAB) in 2016. The SAB recommended that isotopically labelled compounds or stereoisomers related to the parent compound specified in a schedule should be interpreted as belonging to the same schedule. This advice should benefit scientists and diplomats from the CWC’s State Parties to help ensure a consistent approach to their declarations of scheduled chemicals (which in turn supports both the correctness and completeness of declarations under the CWC). Herein, isotopically labelled and stereoisomeric variants of CWC-scheduled chemicals are reviewed, and the impact of the SAB advice in influencing a change to national licensing in one of the State Parties is discussed. This outcome, an update to national licensing governing compliance to an international treaty, serves as an example of the effectiveness of science diplomacy within an international disarmament treaty.

Introduction

The Chemical Weapons Convention (CWC or hereinafter “the Convention”) is an international disarmament treaty banning chemical weapons. The nations (States) party to the treaty are required to destroy any chemical weapon stockpiles and production facilities that they possess and to implement national laws that provide oversight for certain chemicals considered to be relevant to the intent and purpose of the treaty [1]. It is the first disarmament treaty to introduce a verifiable ban on an entire class of weapons of mass destruction. The Convention entered into force on 29 April 1997 and today includes 193 States Parties. This leaves four States outside its obligations: the Democratic People’s Republic of Korea, Egypt, Israel, and South Sudan.

The Convention is implemented by the Organisation for the Prohibition of Chemical Weapons (OPCW) which has its headquarters in The Hague, the Netherlands.[1] The OPCW is an international organisation outside the United Nations system and was awarded the Nobel Peace Prize in 2013 for ‘its extensive efforts to eliminate chemical weapons’ [2]. It fulfils the object and purpose of the Convention and at the beginning of 2018 had verified the destruction of over 96% of the world’s declared stockpile of 72304 metric tonnes of chemical agents [3]. Treaty implementation is supported through evidence-based scientific advice from an independent Scientific Advisory Board (SAB), which serves as input for decision-making by the Director-General and the States Parties. The SAB represents a scientific advisory mechanism for the provision of science advice to support policy making (as opposed to providing advice on policy for science).

The Convention defines chemical weapons through its Article II as:

  1. Toxic chemicals and their precursors, except where intended for purposes not prohibited under this Convention, as long as the types and quantities are consistent with such purposes;

  2. Munitions and devices, specifically designed to cause death or other harm through the toxic properties of those toxic chemicals specified in subparagraph (a), which would be released as a result of the employment of such munitions and devices;

  3. Any equipment specifically designed for use directly in connection with the employment of munitions and devices specified in subparagraph (b)[1].

A “toxic chemical” is “any chemical which through its chemical action on life processes can cause death, temporary incapacitation or permanent harm to humans or animals. This includes all such chemicals, regardless of their origin or of their method of production, and regardless of whether they are produced in facilities, in munitions or elsewhere” [1].

A precursor is any chemical reactant which takes part at any stage in the production by whatever method of a chemical. This includes any key component of a binary or multicomponent chemical system. The “key component” is defined as “the precursor which plays the most important role in determining the toxic properties of the final product and reacts rapidly with other chemicals in the binary or multicomponent system” [1].

Certain toxic chemicals and precursors are subject to verification. They feature in Schedules 1, 2 and 3 in the Annex on Chemicals to the Convention (given in Appendix 1 herein) [4], [5]. The schedules are based mainly on chemicals associated with historical chemical warfare programmes and use, although some toxic chemicals used in the First World War, considered obsolete during the negotiations of the Convention, were excluded.[2] The schedules contain specific chemicals along with families intended to encompass analogues with known or predicted properties similar to those of chemical warfare agents (CWAs) that could pose a risk to the Convention. While a mechanism exists for States Parties to amend the schedules, no proposals for adding new chemicals have been formally put forward since the Convention entered into force, although suggestions by States Parties may soon be forthcoming.[3]

Most of the toxic chemicals and precursors in the schedules relate to three classes of nerve agents (G agents, tabun and analogues, and V agents) and three classes of vesicant (sulfur mustards, Lewisites, and nitrogen mustards) [6]. With the exception of tabun and the nitrogen mustards, these agents accounted for most of the stockpile of toxic chemicals declared worldwide [7]. Other toxic chemicals in the schedules are saxitoxin (a natural product formed by cyanobacteria that is responsible for causing paralytic shellfish poisoning), ricin (a protein toxin found in the castor bean), the central nervous system (CNS) acting chemical 3-quinuclidinyl benzilate (BZ) [8], the organophosphorus pesticide amiton [9], plus toxic industrial chemicals (which include phosgene and hydrogen cyanide), some having been used historically as CWAs. The precursors are based on the known primary production routes to Schedule 1 or Schedule 2 chemicals; however, they do not necessarily cover all the possible synthetic routes. Some chemicals on the schedules can exist as enantiomers and/or diastereomers, but the schedules do not distinguish among these.

The States Parties to the Convention are obligated to: (a) disarm chemically by destroying all stockpiles of chemical weapons, facilities that produced them, and any old or abandoned chemical weapons;2 (b) never to develop, produce, stockpile or use chemical weapons; (c) submit regular declarations to the OPCW on chemical production facilities meeting certain criteria relevant to the CWC within their territories, and on the production, processing, consumption, and import and export of scheduled chemicals; and (d) to allow the OPCW to carry out routine inspections on the territories of States Parties. Given these requirements, the ability to recognise whether a given chemical is subject to the provisions of the Convention is important for States Parties to maintain compliance [10].

This paper reproduces advice on isotopically labelled compounds and stereoisomers provided by the SAB to the Director-General on 28 April 2016 [11], [12], published here with additional background information for those interested in the better understanding of the nuances of how scientific input is brought into policy making. It is intended for a readership of chemists and other scientists with an interest in how science advice influences policy making. A scientific analysis of the relationships between isotopically labelled and stereoisomeric chemicals and those specified in the schedules is provided; and the recommendations by the SAB on how chemicals relevant to Schedules 1, 2 and 3 should be considered in relation to the Convention are given. The paper closes with an example of how the SAB’s advice influenced a change to national licensing of one State Party. We thus provide a case study on how science advice can be used within an international disarmament treaty to strengthen further the objectives of the CWC. We finish by describing future prospects for the advice given in relation to the implementation of the Convention. This paper is the second in a series of scientific publications produced by the SAB this year [13]. These publications represent contributions of scientists from across 25 nations, a demonstration of how international scientific collaboration (“science diplomacy”) can be facilitated through, and lend support to, an international disarmament treaty.

Isotopically labelled chemicals and stereoisomers

To meet obligations under the Convention, and ensure complete and accurate declarations by States Parties – Parts VI, VII and VIII to the CWC’s Annex on Implementation and Verification require that chemicals falling under Schedules 1, 2, and 3 must be clearly identifiable [1]. Some isotopically labelled Schedule 1 and Schedule 2 chemicals, and Schedule 2 chemicals that could exist as distinct stereoisomers (e.g. the stereoisomers of BZ), had presented ambiguity as to how they should be declared [14].

The Convention’s Annex on Chemicals identifies chemicals through a combination of chemical families and/or specific chemical names accompanied by a corresponding Chemical Abstracts Service (CAS) registry number if one has been assigned [14]. The chemical name can be a common name or one standardised according to nomenclature rules established by the International Union of Pure and Applied Chemistry (IUPAC) [4][15]. A CAS number is a unique numerical identifier assigned by the CAS to every chemical substance described in the scientific (or patent) literature from 1957 to today[5][16]. As a CAS number is only assigned if a chemical has appeared in a publication where it was produced or discovered, isotopically labelled scheduled chemicals and stereoisomers of scheduled chemicals prepared, but not published in the scientific literature, will not have had a CAS number assigned to them (the same applies for any chemical whose molecular structure would fall under the Schedules but has not been published in the scientific or patent literature).

CAS numbers are intended to provide a unique, unmistakable identifier for chemicals. However, a chemical will have different CAS numbers assigned to analogues containing isotopic labels. A stereoisomer will also have a different CAS number from that of an isomeric mixture (whether racemic, scalemic, or comprising other stereoisomers, e.g. epimers or diastereomers). The following examples illustrate the ambiguity that could arise [14]:

  1. The nitrogen mustard bis(2-chloroethyl)methylamine (1) (HN2) is listed in Schedule 1.A.06 with CAS registry number 51-75-2. The 14C-isotopically labelled molecule, bis(2-chloroethyl)methyl[14C]amine (2), has not been assigned a CAS registry number. If only the exact name and/or CAS number listed in Schedule 1.A.06 were considered for verification purposes, the 14C-labelled nitrogen mustard might not be identified as a scheduled chemical (see the structures in Fig. 1).

  2. Another example involves three isotopic variations of sarin (Fig. 2): isopropyl methylphosphonofluoridate (3), isopropyl-d7 methylphosphonofluoridate (4), and isopropyl methyl-d3-phosphonofluoridate (5). The first of these is sarin, as listed in Schedule 1.A.01 (with CAS number 107-44-8). The other two are deuterated analogues of sarin. It has been argued that compound 4 should be considered under Schedule 2.B.04 (Precursors: chemicals except for those listed under Schedule 1, containing a phosphorus atom to which is bonded one methyl, ethyl or propyl (normal or iso) group but not further carbon atoms) rather than Schedule 1.A.01 (to which sarin belongs). It has also been argued that analogue 5 should not be considered under any CWC schedule because the “methyl” (of methyl, ethyl, propyl and isopropyl) specified in Schedule 1.A.01 or Schedule 2.B.04 corresponds to “CH3” only, and not to any deuterated or otherwise isotopically labelled version.

  3. BZ highlights the ambiguity for stereoisomers. BZ is listed in Schedule 2.A.03, alongside its chemical name and CAS number 6581-06-2; yet its structure is not shown. BZ can exist as two enantiomers, which have been assigned CAS numbers 62869-69-6 (R-(−)-enantiomer) and 62869-68-5 (S-(+)-enantiomer) (Fig. 3). If only the exact name and/or CAS number listed in Schedule 2.A.03 were considered, stereoisomers might not be identified as scheduled chemicals.

Fig. 1: Nitrogen mustard HN2 (left) and a 14C-labelled analogue (right).
Fig. 1:

Nitrogen mustard HN2 (left) and a 14C-labelled analogue (right).

Fig. 2: Sarin (left) and two deuterated analogues (middle and right).
Fig. 2:

Sarin (left) and two deuterated analogues (middle and right).

Fig. 3: Racemic BZ (left) and its enantiomers (middle and right). The asymmetric carbon atom is marked with an asterisk.
Fig. 3:

Racemic BZ (left) and its enantiomers (middle and right). The asymmetric carbon atom is marked with an asterisk.

The OPCW Director-General’s request

To resolve the ambiguities, the OPCW Director-General requested advice from the SAB[6][14]. The SAB consists of 25 members (Fig. 4) appointed by the Director-General from nominees submitted by States Parties [17], [18], [19], [20]. The members are selected on the strength of their expertise in scientific fields relevant to the implementation of the Convention and are from research organisations, chemical industry, defence, academia and/or military. Only citizens of States Parties are eligible to serve and do so in their individual capacity as independent experts. The term of office is 3 years and each member may serve for up to two consecutive terms. The Director-General makes the SAB’s reports and his responses to these publically available [17]. This time the advice requested by the Director-General was to:

Fig. 4: The SAB with the Director-General at the Twenty-Third Session of the Board on 18 April 2016 [11]. The SAB endorsed the report containing the advice on isotopically labelled chemicals and stereoisomers then. From left to right: (Back Row) Professor Slawomir Neffe (Poland), Dr. Jonathan E. Forman (OPCW Technical Secretariat, Science Policy Adviser), Professor Zrinka Kovarik (Croatia), Professor Ponnadurai Ramasami (Mauritius), Dr. Koji Takeuchi (Japan), Professor Roberto Martínez-Álvarez (Spain), Dr Augustin Baulig (France), Dr Robert Mikulak (United States of America), Professor Volodymyr Zaitsev (Ukraine), Mr Francois Mauritz van Straten (South Africa), Dr Abdullah Saeed Al-Amri (Saudi Arabia), Dr Christophe Curty (Switzerland), Dr David Gonzalez (Uruguay), Professor Ferruccio Trifirò (Italy); (Front Row) Professor Isel Pascual Alonso (Cuba), Professor Mongia Said Zina (Tunisia), Ms Farhat Waqar (Pakistan), Professor Mohammad Abdollahi (Islamic Republic of Iran), Dr Christopher M. Timperley (United Kingdom, SAB Chair), His Excellency Ambassador Ahmet Üzümcü (OPCW Director-General), Mr Cheng Tang (China, SAB Vice-Chair), Dr Nicia Maria Fusaro Mourão (Brazil), Professor Paula Vanninen (Finland), Dr Veronica Borrett (Australia). The other SAB members – Dr Syed K. Raza (India), Professor Flerida Cariño (Philippines) and Mr Valentin Rubaylo (Russian Federation) – were unable to attend.
Fig. 4:

The SAB with the Director-General at the Twenty-Third Session of the Board on 18 April 2016 [11]. The SAB endorsed the report containing the advice on isotopically labelled chemicals and stereoisomers then. From left to right: (Back Row) Professor Slawomir Neffe (Poland), Dr. Jonathan E. Forman (OPCW Technical Secretariat, Science Policy Adviser), Professor Zrinka Kovarik (Croatia), Professor Ponnadurai Ramasami (Mauritius), Dr. Koji Takeuchi (Japan), Professor Roberto Martínez-Álvarez (Spain), Dr Augustin Baulig (France), Dr Robert Mikulak (United States of America), Professor Volodymyr Zaitsev (Ukraine), Mr Francois Mauritz van Straten (South Africa), Dr Abdullah Saeed Al-Amri (Saudi Arabia), Dr Christophe Curty (Switzerland), Dr David Gonzalez (Uruguay), Professor Ferruccio Trifirò (Italy); (Front Row) Professor Isel Pascual Alonso (Cuba), Professor Mongia Said Zina (Tunisia), Ms Farhat Waqar (Pakistan), Professor Mohammad Abdollahi (Islamic Republic of Iran), Dr Christopher M. Timperley (United Kingdom, SAB Chair), His Excellency Ambassador Ahmet Üzümcü (OPCW Director-General), Mr Cheng Tang (China, SAB Vice-Chair), Dr Nicia Maria Fusaro Mourão (Brazil), Professor Paula Vanninen (Finland), Dr Veronica Borrett (Australia). The other SAB members – Dr Syed K. Raza (India), Professor Flerida Cariño (Philippines) and Mr Valentin Rubaylo (Russian Federation) – were unable to attend.

  1. Provide technical recommendations on isotopic labelling of chemicals relevant to Schedule 1, 2 and 3 under the Convention;

  2. Assess whether the chemical properties of a chemical are altered, when subject to isotopic labelling, in a manner that would affect its relevance to the schedules of chemicals under the Convention; and

  3. Make technical recommendations on how stereoisomers of chemicals relevant to Schedules 1, 2 and 3 should be considered in relation to the Convention.

The Director-General noted that the SAB, in making its response, should recall previous advice from February 2008 [21] and October 2012 [22], which pointed out “there is not necessarily a one-to-one relationship between CAS registry numbers and chemical structures”, and that CAS registry numbers should be considered not as absolute determinants of whether chemicals are included in the schedules, but as aids to identification.

The advice from the SAB

In response to the Director-General’s request, the SAB provided two recommendations to the Director-General and States Parties (as stated in Ref. 12]). These are reproduced here:

Recommendation 1

The molecular parent structure of a chemical should determine whether it is covered by a schedule entry. This is because:

  1. It is inappropriate to rely upon CAS numbers to define chemicals covered by the schedules. Although relevant as aids to declaration and verification, CAS numbers should not be used as the means to identify a chemical, or to determine whether a chemical is included in, or excluded from, a schedule;

  2. Thus, if a chemical is included within a schedule, then all possible isotopically-labelled forms and stereoisomers of that chemical should be included, irrespective of whether or not they have been assigned a CAS number or have CAS numbers different to those shown in the Annex on Chemicals to the Convention. The isotopically labelled compound or stereoisomer related to the parent chemical specified in the schedule should be interpreted as belonging to the same schedule; and

  3. This advice is consistent with previous SAB views on this topic [21], [22].

Recommendation 2

Inclusion of appropriate analytical data in the OPCW Central Analytical Database (OCAD) for isotopically labelled relatives of scheduled compounds and stereoisomers, where available, is recommended.[7]

Findings

The evidence used to give the advice was gathered from the specialist knowledge of the SAB and the scientific literature. Information reviewed and conclusions drawn are described next.

Isotopically labelled scheduled chemicals

Isotopic labelling is used to develop analytical methods for CWAs and precursors [23], [24], [25], [26], [27], [28], [29] and to study the mechanism of action of CWAs [30] and potential medical treatments [31]. The mechanism of action of CWAs is generally understood, although the precise mechanism of vesication by the sulfur and nitrogen mustards, and Lewisites 1 and 2 (Lewisite 3 is not vesicant), is yet to be elucidated, despite research over decades [32]. Isotope substitution is regarded as the smallest structural change in a molecule. Thus, isotopically labelled CWAs are presumably as hazardous as their unlabelled counterparts listed in the schedules.

The schedules of the Convention provide lists of chemicals that are subject to oversight, which would logically be applied to bulk samples of such chemicals (in small quantity for allowed uses of Schedule 1 chemicals and in large industrial-scale amounts for many of the Schedule 3 chemicals). Unless prepared in a way that enriches a certain isotope of an atom in the molecule, a given chemical does not exist solely as composites of these most abundant isotopes (e.g. 1H, 12C, 15N, 16O, 31P). Rather, it exists as a mixture of molecules that contain different ratios of isotopes, and the ratios of each isotope will depend on its natural abundance. CAS numbers assigned to molecules that are not designated as enriched in a specific isotope of one or more of the atoms in the molecular structure, for regulatory purposes would be associated with samples containing natural abundances and ratios of the isotopes. A good example is the blister agent sulfur mustard – bis(2-chloroethyl)sulfide – in Schedule 1.A.04 with CAS number 505-60-2. This number is understood to refer to the structure containing the most abundant isotope of sulfur (32S), which constitutes ~95% of pure sulfur mustard. However, the sample will also contain ~5% of sulfur mustard molecules containing other natural sulfur isotopes (33S, 34S, 35S) (Fig. 5) [33]. 33S- and 34S-sulfur mustard have not been assigned CAS numbers (which is indicative of molecules enriched in these isotopes of sulfur never having had their preparation reported in the scientific literature). 35S-Sulfur mustard has been isolated [34] and assigned CAS number 6755-76-6, which differs from the CAS number of sulfur mustard in Schedule 1.A.04. This could mean that in a control list that uses the CAS numbers specified in the schedules of the Convention as identifiers for chemicals, 35S-sulfur mustard might not be identified for declaration, even though it is a minor constituent of the sulfur mustard identified in Schedule 1.A.04 by CAS number 505-60-2.

Fig. 5: Isotopically labelled sulfur mustards. Percentages of CAS 505-60-2 constituents were calculated from the natural abundances of isotopes of sulfur [33].
Fig. 5:

Isotopically labelled sulfur mustards. Percentages of CAS 505-60-2 constituents were calculated from the natural abundances of isotopes of sulfur [33].

If the only chemicals considered to be covered by Schedule 1, for example, were those with CAS numbers listed in the Annex on Chemicals, then the deuterium (d)-labelled sulfur mustards [34], [35], [36], [37], [38], [39], [40] in Fig. 6 – all of which are likely to be as hazardous as the sulfur mustard in Schedule 1.A.04 under CAS 505-60-2 – might not be considered to be scheduled chemicals. This would seem unacceptable as isotopically labelled sulfur mustards could then be developed, produced and stockpiled, arguably legitimately, under the Convention. This would contravene the spirit of the Convention and removing such ambiguities would strengthen further its intent and purpose.

Fig. 6: Deuterated sulfur mustards. D denotes a deuterium atom in place of a hydrogen atom [34], [35], [36], [37], [38], [39], [40].
Fig. 6:

Deuterated sulfur mustards. D denotes a deuterium atom in place of a hydrogen atom [34], [35], [36], [37], [38], [39], [40].

Furthermore, reliance on CAS numbers to identify scheduled chemicals would not address identification of mixtures of toxic chemicals for accurate declaration. For example, a mixture of 60:40 percent by weight of sulfur mustard HD (Schedule 1.A.04, CAS 505-60-2) and O-mustard or T (Schedule 1.A.04, CAS 63918-89-8) was used to fill munitions in past chemical warfare programmes [41], [42]. This so-called HT mixture has a CAS number (Fig. 7a) that is absent from the schedules. Another example is a mixture of sulfur mustard (Schedule 1.A.04, CAS 505-60-2) and Lewisite 1 (L) (Schedule 1.A.05, CAS 541-25-3) which was also weaponised historically [43], [44], [45], [46]. This mixture has a CAS number different from those CAS numbers of its pure components (Fig. 7b).

Fig. 7: (a) HD and T when pure have separate CAS numbers but a 60:40 mixture has been allocated a different CAS number. (b) HD and L when pure have separate CAS numbers but a mixture has been assigned a different CAS number.
Fig. 7:

(a) HD and T when pure have separate CAS numbers but a 60:40 mixture has been allocated a different CAS number. (b) HD and L when pure have separate CAS numbers but a mixture has been assigned a different CAS number.

Another illustrative example is the route to sarin production from methylphosphonic dichloride [47], [48] through methylphosphonic difluoride [49] to sarin (Fig. 8). Isotopically labelled counterparts are shown underneath. All three have different CAS numbers to those present in the schedules for the unlabelled variants. Therefore they might not be identified as scheduled chemicals, yet sarin-d3 is likely to be just as hazardous as sarin.

Fig. 8: Non-deuterated and deuterated precursors to sarin, and non-deuterated and deuterated sarin. All have different CAS numbers.
Fig. 8:

Non-deuterated and deuterated precursors to sarin, and non-deuterated and deuterated sarin. All have different CAS numbers.

Schedule 1.A.01, containing sarin as a member of the O-alkyl alkylphosphonofluoridate family of chemicals, defines only structures with P-methyl, ethyl, and n- or i-propyl groups; these could be interpreted to comprise CH3, C2H5, and C3H7 and not deuterated variants, for example CD3, C2D5, and C3D7. This interpretation could be applied to all such scheduled chemicals. To someone well versed in chemistry, this may seem unlikely. However, it must be appreciated that the end users of the schedules may be regulatory bodies and not scientists. Thus, advice for these users would be that all isotopically labelled versions of scheduled chemicals should be considered to belong to the same schedule as the parent structure.

Capturing these isotopically labelled chemicals within the schedules requires acknowledging that they are identical for the purposes of declaration to their unlabelled counterparts already specified in the schedules.

Stereoisomers of scheduled chemicals

Some toxic chemicals can exist as enantiomers (e.g. organophosphorus nerve agents) or diastereoisomers (e.g. the nerve agent soman) [50]. Nerve agent stereoisomers – enantiomers and/or diastereoisomers – show differences in biological activity (Table 1). The (+)-enantiomer is usually a weaker inhibitor of the enzyme acetylcholinesterase (AChE), whose inhibition disrupts the normal functioning of the nervous system, and less toxic than the (−)-enantiomer. The racemic mixture, a 1:1 molar ratio of each enantiomer, is denoted by the prefix (±) and has a biological activity from the sum contribution of the two enantiomers.

Table 1:

Effect of nerve agent stereochemistry on the AChE inhibition rate constant and the acute lethality expressed as an LD50 value [47], [51, 52, 53].

StereoisomerRate constant for AChE inhibition at 25°C (M−1 min−1)aLD50 mouse (μg kg−1)
(+)-tabun4×105837b
(−)-tabun2×106119b
(±)-tabunNA208b
(+)-sarin<3×103dNA
(−)-sarin1×10741b
(±)-sarinNA83b
C(+)P(+)-soman<5×103>5000c
C(−)P(+)-soman<5×103>2000c
C(+)P(−)-soman3×10899c
C(−)P(−)-soman2×10838c
C(±)P(±)-somanNA156c
(+)-VX2×106165b
(−)-VX4×10813b
(±)-VXNA20b
  1. LD50 is the lethal dose that kills half a group of test animals. aRate constants for tabun and soman isomers were measured with electric eel AChE at pH 7.5 whereas those for sarin and VX enantiomers were obtained with bovine erythrocyte AChE. bIntravenous administration. cSubcutaneous administration. dEstimated from an experiment with optically enriched (+)-sarin (64% enantiomeric excess). Note that the (−)-cyclosarin enantiomer, where the P-isopropyloxy group in sarin is replaced by a cyclohexyloxy group, inhibits AChE more strongly than (±)-cyclosarin and is the most toxic isomer [52], in line with the trend revealed in the table. NA denotes that the data were not available.

Standard synthetic pathways to CWAs are non-stereoselective and produce a racemic mixture of stereoisomers. Thus, one stereoisomer is naturally associated with the other, and should not be viewed independently of the other for the purposes of the schedules.

Sarin listed in Schedule 1.A.01 and defined by CAS number 107-44-8 is understood to be a racemic mixture, comprising an approximately equal mixture of its enantiomers [54], [55], [56], [57], [58]. This mixture is denoted (±)-sarin. However, pure enantiomers have different CAS numbers: 6171-94-4 for the more toxic (R)-(−)-sarin and 6171-93-3 for the less toxic (S)-(+)-sarin (Fig. 9). As both are highly toxic and have similar properties to the (±)-material specified in Schedule 1.A.01, it would be inconsistent with the intent and purpose of the Convention to treat them differently from the racemic mixture.

Fig. 9: Sarin and its two enantiomers have been assigned different CAS numbers.
Fig. 9:

Sarin and its two enantiomers have been assigned different CAS numbers.

Another example is provided by BZ [59]. It features in Schedule 2.A.03 under CAS number 6581-06-2. It can exist as enantiomers: (R)-(−)-BZ and (S)-(+)-BZ (however, producing this material under non-enantioselective conditions would produce a racemic mixture) (Fig. 3). Both enantiomers are capable of causing behavioural effects in humans (note that (R)-(−)-BZ is at least 20 times more potent than its (S)-(+)-stereoisomer in causing behavioural effects in dogs after subcutaneous administration [60]). Despite one enantiomer being more potent than the other, both can be used to affect life processes, and methods of production can potentially produce both enantiomers. For regulatory purposes the enantiomers of BZ would both fall under Schedule 2.A.03.

These examples are illustrative and more could be provided. However, the SAB did not find this necessary as the general concept was unchanged from example to example.

Conclusions

In its advice to the Director-General, the SAB concluded that isotopically labelled or stereoisomeric variants of scheduled chemicals should be interpreted as belonging to the schedule that includes the parent structure [12]. And that the structure of a chemical, regardless of its isotopic composition or spatial orientation of atoms, should determine whether that chemical falls within the schedules of the Convention. A principal reason for this was that the chemical functionality that makes the scheduled chemical toxic, or allows it to be a precursor to a toxic chemical, is still present in its isotopically labelled variants and different stereoisomers. Because of the very large number of isotopically labelled and stereoisomeric scheduled chemicals theoretically obtainable, it is inappropriate to rely solely on the CAS numbers specified in the schedules for identifying scheduled chemicals. The SAB also concluded that with the parent chemicals on the schedules, States Parties should treat isotopically labelled and stereoisomeric forms of such chemicals appropriately for declaration and verification purposes.

The importance of effective science-policymaker engagement [10], [61] was recognised in 2014 by the launch of an initiative within the OPCW entitled “Science for Diplomats”. This initiative institutionalised the holding of regularly scheduled lectures at OPCW Headquarters on scientific topics relevant to the Convention [62]. The advice provided to the Director-General by the SAB on isotopic labels, stereoisomers, and scheduled chemicals, was briefed to the States Parties in July 2016 at one of these events [63] to convey to diplomats the importance of the subject, and why nuances associated with molecular structures and CAS numbers, something that may seem abstract to their day to day considerations, were actually important for the implementation of the Convention (Fig. 10).

Fig. 10: Dr. Jonathan E. Forman, OPCW Science Policy Adviser and Secretary to the SAB, briefed the CWC States Parties on the SAB’s advice on isotopic labels, stereoisomers, and scheduled chemicals, on 13 July 2016 at a “Science for Diplomats” event (left) during the Eighty-Second Session of the OPCW Executive Council [63]. Ball-and-stick molecular models prepared by OPCW interns (top right) were provided to diplomats (bottom right) who were taught to recognise the enantiomers of sarin to illustrate their relative spatial characteristics and non-superimposable nature, to understand that they are not the same molecules, and that both should be covered by Schedule 1 of the CWC, and declared as such.
Fig. 10:

Dr. Jonathan E. Forman, OPCW Science Policy Adviser and Secretary to the SAB, briefed the CWC States Parties on the SAB’s advice on isotopic labels, stereoisomers, and scheduled chemicals, on 13 July 2016 at a “Science for Diplomats” event (left) during the Eighty-Second Session of the OPCW Executive Council [63]. Ball-and-stick molecular models prepared by OPCW interns (top right) were provided to diplomats (bottom right) who were taught to recognise the enantiomers of sarin to illustrate their relative spatial characteristics and non-superimposable nature, to understand that they are not the same molecules, and that both should be covered by Schedule 1 of the CWC, and declared as such.

Impact of the advice from the SAB: the change of UK legislation as an example

Teaching stereochemistry to government officials from 193 States charged with overseeing a disarmament treaty may seem like a distraction from the issues they might need to be focused on, yet this advice helped prompt a change to national licensing within a State Party of the Convention, namely the United Kingdom of Great Britain and Northern Ireland (the UK). In contextualising this outcome, we will start with a description of a National Authority (NA) to the Convention and the licensing policy adopted within its ambit.[8]

All States Parties are required to designate a NA to oversee implementation of the Convention and ensure its obligations are met.[9] The UK NA is based in the Department for Business, Energy & Industrial Strategy (BEIS) in London.[10] BEIS helps safeguard the peaceful applications of chemistry. It oversees implementation of the Convention in the UK, Crown Dependencies and Overseas Territories, in accordance with the provisions of the UK Chemical Weapons Act of 1996 [64]. This legislation places legal requirements on all entities (including companies, universities, transport and other bodies) and individuals that work with certain toxic chemicals within the UK.

Through the NA, the UK expanded in 2017 its licensing policy on chemicals that fall under Schedule 1 of the CWC [65] to include chemicals that were not specifically listed in Schedule 1 under a particular CAS number, but that shared a chemical structure with those that did. This approach was influenced by the SAB’s advice, technical advice from scientific advisers at Dstl Porton Down, legal advice obtained nationally, and the results of a consultation exercise with UK stakeholders.

Fundamental to the objectives of the CWC, and the Schedule 1 licensing regime, are chemicals which can be (or have been) weaponised falling within its scope, and enabling NAs to tightly control possession and use of such chemicals. The UK NA wished to ensure that the licensing system was applied in a technically consistent way, so that chemicals with the same structures, names and toxic properties as chemicals explicitly listed in Schedule 1 were licensable, even if they had different CAS numbers. The UK now considers the molecular structure of a chemical to determine whether it is covered by Schedule 1. Therefore, isotopically labelled analogues, stereoisomers (both optical and geometric), and corresponding salts are licensable (Table 2). The inclusion of salts has significance as previous advice from the SAB recommended that salts of Schedule 1 chemicals should not be considered as non-scheduled chemicals [66], which may not always be the case under regulatory systems that strictly adhere to the exact text of the schedules of the Convention.

Table 2:

Summary of which chemicals under each Schedule 1 section have been licensable since April 2017 in the UK: those that should be licensed are indicated by a cross [65].

ScheduleIsotopically labelled analogueCorresponding saltsStereoisomers
1.A.01

G agents
××
1.A.02

Tabun and analogues
××
1.A.03

V agentsa
×××
1.A.04

Sulfur mustards
×
1.A.05

Lewisites
××
1.A.06

Nitrogen mustards
××
1.A.07

Saxitoxin
×××
1.A.08

Ricin
×
1.B.09

Alkylphosphonyl difluorides

(e.g. DF)
×
1.B.10

O-Alkyl O-2-dialkylaminoethyl alkylphosphonites (e.g. QL)a
××
1.B.11

Chlorosarin
××
1.B.12

Chlorosoman
××
  1. aThe CWC schedules for these chemicals include the corresponding protonated salts [1].

To prevent over-burdensome and unnecessary licensing, to ensure human safety and support medical research, the UK NA implemented a number of limited exemptions [65]. These were necessary to avoid impeding the legitimate transfer, possession and/or use of, for example, paralytic shellfish poisoning diagnostic kits (which contain the Schedule 1 chemical saxitoxin) and some cancer treatments which can contain very small amounts of particular versions of Schedule 1 chemicals (for example, nitrogen mustard HN2), as well as contaminated items such as clothing and environmental samples which might contain traces of Schedule 1 chemicals. The changes to the UK’s Schedule 1 licensing regime, including the exemptions, took effect from April 2017.

Outlook and future prospects

Every 5 years, the OPCW holds a Special Session of States Parties to review the operation of the Convention.[11] For this, the SAB prepares a report on developments in science and technology, for the OPCW Director-General and the States Parties.[12] The next such session – the Fourth Review Conference (RC-4) – will be held in November 2018.

Building on recommendation 1 herein (Section Recommendation 1”), the SAB report to RC-4 advises against relying solely upon CAS numbers to define chemicals covered by the schedules: ‘Although relevant as aids to declaration and verification, CAS numbers are not the only means to identify a chemical or determine whether a chemical is included in or excluded from a schedule’ [66] The same report also advises that: ‘To ensure the consistency of declarations, if a chemical is included within a schedule, then all possible isotopically-labelled forms and stereoisomers of that chemical should be included, irrespective of whether or not they have been assigned a CAS number or have CAS numbers different to those shown in the Annex on Chemicals of the Convention. The isotopically-labelled compound or stereoisomer related to the parent chemical specified in the schedule should be interpreted as belonging to the same schedule’ [66].

Building on recommendation 2 herein (Section Recommendation 2”), the SAB report to RC-4 states that: ‘Appropriate analytical data for chemicals that may pose a risk to the Convention or that are needed to help differentiate permitted activities from prohibited activities should be added to the OCAD. This could include isotopically-labelled relatives and stereoisomers of scheduled compounds, salts of scheduled chemicals, toxic industrial chemicals, CNS-acting chemicals, riot control chemicals, bioregulators, toxins, and unscheduled chemicals that have been identified as posing a risk to the Convention’ [66].

The SAB hopes that these recommendations will after due consideration by the States Parties, translate into policies that will help to make the world a safer place through strengthening the verification mechanism of the Convention, which has been instrumental to its success to date.


Article note

A special issue containing invited papers on Innovative Technologies for Chemical Security, based on work done within the framework of the Chemical Weapons Convention.


Acknowledgements

The SAB thanks Ambassador Ahmet Üzümcü for supporting the Board and providing its output to States Parties to inform their decision making. The SAB expresses its gratitude to Dr. Sarah Clapham, Dr. Jim McGilly and Mr. Matthew Brooks of Dstl, and to Mr. Terry Dance and Mr. Craig Wallbank of the UK National Authority in BEIS, for information and helpful feedback, especially on the change of licensing of scheduled chemicals in the UK. The SAB also acknowledges Ms. Marlene Payva, for her skillful assistance to the Board, the European Union for providing funding for activities of the Board, and the International Union of Pure and Applied Chemistry for its support during the run-up to RC-4 and the three Review Conferences held previously, to which it provided substantial scientific input [67], [68], [69].

Appendix 1:

The schedules of chemicals of the Chemical Weapons Convention.

Schedule 1
The following criteria shall be taken into account in considering whether a toxic chemical or precursor should be included in Schedule 1:

(a) It has been developed, produced, stockpiled or used as a chemical weapon as defined in Article II;

(b) It poses otherwise a high risk to the object and purpose of this Convention by virtue of its high potential for use in activities prohibited under this Convention because one or more of the following conditions are met:

 (i) It possesses a chemical structure closely related to that of other toxic chemicals listed in Schedule 1, and has, or can be expected to have, comparable properties;

 (ii) It possesses such lethal or incapacitating toxicity as well as other properties that would enable it to be used as a chemical weapon;

 (iii) It may be used as a precursor in the final single technological stage of production of a toxic chemical listed in Schedule 1, regardless of whether this stage takes place in facilities, in munitions or elsewhere;

(c) It has little or no use for purposes not prohibited under this Convention
No.Chemical/sCAS number
A. Toxic chemicals
Nerve agents
1O-Alkyl (≤C10, incl. cycloalkyl) alkyl (Me, Et, n-Pr or i-Pr)-phosphonofluoridates

Commonly known as G agents (but not GA)

e.g. Sarin: O-Isopropyl methylphosphonofluoridate

107-44-8
Soman: O-Pinacolyl methylphosphonofluoridate

96-64-0
2O-Alkyl (≤C10, incl. cycloalkyl) N,N-dialkyl (Me, Et, n-Pr or i-Pr) phosphoramidocyanidates

Tabun (GA) and analogues



e.g. Tabun: O-Ethyl N,N-dimethyl phosphoramidocyanidate

77-81-6
3O-Alkyl (H or ≤C10, incl. cycloalkyl) S-2-dialkyl (Me, Et, n-Pr or i-Pr)-aminoethyl alkyl (Me, Et, n-Pr or i-Pr) phosphonothiolates

Commonly known as V agents



and corresponding alkylated or protonated salts, e.g.

VX: O-Ethyl S-2-diisopropylaminoethyl methylphosphonothiolate



Note! Schedule 1.A.03 includes partly hydrolysed V agents, as H is also included in the O-alkyl definition
50782-69-9
Vesicants
4Sulfur mustards:

2-Chloroethylchloromethylsulfide

Mustard gas: bis(2-chloroethyl)sulfide

Bis(2-chloroethylthio)methane

Sesquimustard: 1,2-bis(2-chloroethylthio)ethane

1,3-Bis(2-chloroethylthio)-n-propane

1,4-Bis(2-chloroethylthio)-n-butane

1,5-Bis(2-chloroethylthio)-n-pentane

Bis(2-chloroethylthiomethyl)ether

O-Mustard: bis(2-chloroethylthioethyl)ether



2625-76-5

505-60-2

63869-13-6

3563-36-8

63905-10-2

142868-93-7

142868-94-8

63918-90-1

63918-89-8
5Lewisites

Lewisite 1: 2-chlorovinyldichloroarsine

Lewisite 2: bis(2-chlorovinyl)chloroarsine

Lewisite 3: Tris(2-chlorovinyl)arsine

Lewisites 2 and 3 are impurities in Lewisite 1



541-25-3

40334-69-8

40334-70-1
6Nitrogen mustards

HN1: bis(2-chloroethyl)ethylamine

HN2: bis(2-chloroethyl)methylamine

HN3: Tris(2-chloroethyl)amine

Salts of nitrogen mustard are not included



538-07-8

51-75-2

555-77-1
7Saxitoxin

A marine toxin; salts or analogues are not included [74]

35523-89-8
8Ricin

A heterogeneous glycoprotein extracted from the castor bean, approximate molecular mass of 65 kDa.

The SAB recommended to the OPCW Director-General in 2009 the following definition be adopted for verification purposes:

‘All forms of ricin originating from Ricinus communis, including any variations in the structure of the molecule arising from natural processes, or man-made modification designed to maintain or enhance toxicity, are to be considered ricin as long as they conform to the basic ‘native’ bipartite molecular structure of ricin that is required for mammalian toxicity, i.e. A and B chains linked only by a disulfide bond (A-S-S-B). Once the inter-chain S-S bond is broken or the protein denatured, it is no longer ricin’ [75]
9009-86-3
B. Precursors
9Alkyl (Me, Et, n-Pr or i-Pr) phosphonyl difluorides



e.g. DF: Methylphosphonyl difluoride

Also known as methylphosphonic difluoride



676-99-3
10O-Alkyl (H or ≤C10, incl. cycloalkyl) O-2-dialkyl (Me, Et, n-Pr or i-Pr)-aminoethyl alkyl (Me, Et, n-Pr or i-Pr) phosphonites



and corresponding alkylated or protonated salts

e.g. QL: O-Ethyl O-2-diisopropylaminoethyl methylphosphonate

57856-11-8
11Chlorosarin: O-Isopropyl methylphosphonochloridate1445-76-7
12Chlorosoman: O-Pinacolyl methylphosphonochloridate7040-57-5
Schedule 2
The following criteria shall be taken into account in considering whether a toxic chemical not listed in Schedule 1 or a precursor to a Schedule 1 chemical or to a chemical listed in Schedule 2, part A, should be included in Schedule 2:

(a) It poses a significant risk to the object and purpose of this Convention because it possesses such lethal or incapacitating toxicity as well as other properties that could enable it to be used as a chemical weapon;

(b) It may be used as a precursor in one of the chemical reactions at the final stage of formation of a chemical listed in Schedule 1 or Schedule 2, part A;

(c) It poses a significant risk to the object and purpose of this Convention by virtue of its importance in the production of a chemical listed in Schedule 1 or Schedule 2, part A;

(d) It is not produced in large commercial quantities for purposes not prohibited under this Convention.
No.Chemical/sCAS number
A. Toxic chemicals
1Amiton: O,O-Diethyl S-[2-(diethylamino)ethyl] phosphorothiolate



and corresponding alkylated and protonated salts

78-53-5
2PFIB: 1,1,3,3,3-Pentafluoro-2-(trifluoromethyl)-1-propene

A toxic industrial by-product of fluoropolymer manufacture [76], [77], [78], [79], [80]

382-21-8
3BZ: 3-Quinuclidinyl benzilate

A previously weaponized incapacitant/CNS-acting chemical

6581-06-2
B. Precursors
4Chemicals, except for those listed in Schedule 1, containing a phosphorus atom to which is bonded one methyl, ethyl or propyl (normal or iso) group but not further carbon atoms, e.g.

Methylphosphonyl dichloride

Also known as methylphosphonic dichloride (DC)





676-97-1
Dimethyl methylphosphonate

756-79-6
Exemption: Fonofos: O-Ethyl S-phenyl ethylphosphonothiolothionate

Commercial pesticide



Note! This schedule defines only one substituent (alkyl) on phosphorus and includes P(III) and P(V) chemicals; it therefore includes an unlimited set of compounds.
944-22-9
5N,N-Dialkyl (Me, Et, n-Pr or i-Pr) phosphoramidic dihalides

Precursors for Schedule 1.A.02 chemicals, tabun and analogues

6Dialkyl (Me, Et, n-Pr or i-Pr) N,N-dialkyl (Me, Et, n-Pr or i-Pr)-phosphoramidates

Possible precursors for, or impurities, in Schedule 1.A.02 chemicals

7Arsenic trichloride

Precursor for Schedule 1.A.05 chemicals, Lewisites

7784-34-1
82,2-Diphenyl-2-hydroxyacetic acid

Precursor for BZ

76-93-7
9Quinuclidin-3-ol

Precursor for BZ

1619-34-7
10N,N-Dialkyl (Me, Et, n-Pr or i-Pr) aminoethyl-2-chlorides and corresponding protonated salts

Precursors for Schedule 1.A.03 chemicals, V agents

11N,N-Dialkyl (Me, Et, n-Pr or i-Pr) aminoethane-2-ols and corresponding protonated salts

Precursors for Schedule 1.A.03 chemicals, V agents

Exemptions:

N,N-Dimethylaminoethanol and corresponding protonated salts



108-01-0
N,N-Diethylaminoethanol and corresponding protonated salts



These both have widespread industrial uses. Based on discussions after OPCW Proficiency Tests these chemicals are considered relevant and should be reported in a typical test as non-scheduled degradation products of V agents [6].
100-37-8
12N,N-Dialkyl (Me, Et, n-Pr or i-Pr) aminoethane-2-thiols

Precursors for Schedule 1.A.03 chemicals, V agents



and corresponding protonated salts

13Thiodiglycol: bis(2-hydroxyethyl)sulfide

Precursor for sulfur mustard

111-48-8
14Pinacolyl alcohol: 3,3-Dimethylbutan-2-ol

464-07-3
Schedule 3
The following criteria shall be taken into account in considering whether a toxic chemical or precursor, not listed in other Schedules, should be included in Schedule 3:

(a) It has been produced, stockpiled or used as a chemical weapon;

(b) It poses otherwise a risk to the object and purpose of this Convention because it possesses such lethal or incapacitating toxicity as well as other properties that might enable it to be used as a chemical weapon;

(c) It poses a risk to the object and purpose of this Convention by virtue of its importance in the production of one or more chemicals listed in Schedule 1 or Schedule 2, part B;

(d) It may be produced in large commercial quantities for purposes not prohibited under this Convention.
No.ChemicalCAS number
A. Toxic chemicals
1Phosgene: Carbonyl dichloride

75-44-5
2Cyanogen chloride

506-77-4
3Hydrogen cyanide

74-90-8
4Chloropicrin: Trichloronitromethane

76-06-2
B. Precursors
5Phosphorus oxychloride

10025-87-3
6Phosphorus trichloride

7719-12-2
7Phosphorus pentachloride

10026-13-8
8Trimethyl phosphite

121-45-9
9Triethyl phosphite

122-52-1
10Dimethyl phosphite

868-85-9
11Diethyl phosphite

762-04-9
12Sulfur monochloride

10025-67-9
13Sulfur dichloride

10545-99-0
14Thionyl chloride

7719-09-7
15Ethyldiethanolamine

139-87-7
16Methyldiethanolamine

105-59-9
17Triethanolamine

102-71-6
  1. The schedules above list toxic chemicals and their precursors and are taken from the Convention [1], [4]. These schedules identify chemicals for the application of verification measures. The guidelines for inclusion in each schedule are also provided. Chemical structures, which are not provided in the text of the CWC, have been added by the authors for ease of reference, and additional comments in italics.

References

[1] Convention on the Prohibition of the Development, Production, Stockpiling and Use of Chemical Weapons and on their Destruction, Organisation for the Prohibition of Chemical Weapons (OPCW), The Hague, The Netherlands, 1997. Available at https://www.opcw.org/chemical-weapons-convention/, accessed on 1 June 2018.Search in Google Scholar

[2] For details of the award of the 2013 Nobel Peace Prize to the OPCW, see the OPCW public website: https://www.opcw.org/special-sections/nobel-peace-prize-2013/, accessed on 1 June 2018.Search in Google Scholar

[3] The statistics in this sentence were taken from the homepage of the OPCW public website at https://www.opcw.org/, accessed on 1 June 2018.Search in Google Scholar

[4] The Annex on Chemicals to the CWC appears at www.opcw.org/chemical-weapons-convention/annexes/annex-on-chemicals/, accessed on 1 June 2018.Search in Google Scholar

[5] An infographic of the schedules is available to download free-of-charge from www.opcw.org/fileadmin/OPCW/Science_Technology/Guide_to_Schedules.pdf, accessed on 1 June 2018.Search in Google Scholar

[6] R. M. Black, C. M. Timperley, H. Kiljunen. Chemicals, Chapter III, Section 1 General, Part A Introduction, ROP I-A-III, in: Recommended Operating Procedures for Analysis in the Verification of Chemical Disarmament 2017 Edition (The Blue Book), Part 1, The Ministry of Foreign Affairs of Finland, VERIFIN, University of Helsinki, Finland, pp. 5–31 (2017).Search in Google Scholar

[7] R. M. Black. Development, historical use and properties of chemical warfare agents, in: Chemical Warfare Toxicology Volume 1: Fundamental Aspects; F. Worek, J. Jenner, H. Thiermann (eds.); The Royal Society of Chemistry, Cambridge, UK, Chapter 1, pp. 1–28 (2016).Search in Google Scholar

[8] R. J. Mathews. Pure Appl. Chem.90, 1559 (2018).10.1515/pac-2018-0502Search in Google Scholar

[9] C. M. Timperley, Highly-toxic fluorine compounds, in: Fascinated by Fluorine – Fluorine Chemistry at the Millennium, R. E. Banks (ed.), Elsevier, Oxford, UK, Chapter 29, pp. 499–538 (2000).10.1016/B978-008043405-6/50040-2Search in Google Scholar

[10] J. E. Forman, C. M. Timperley. Chemical disarmament in a technologically evolving world, in: Responsible Conduct and Ethical Practice in Chemical Sciences Research, Safety, Security, Education and Risk Management: The Catalytic Role of the Professional/Learned Society, American Chemical Society Publication, Washington, D.C., USA (2018).Search in Google Scholar

[11] OPCW Scientific Advisory Board, Report of the Twenty-Third Session held on 18–22 April 2016, SAB-23/1 of 22 April 2016, pp. 21–22. The meeting report is available at https://www.opcw.org/fileadmin/OPCW/SAB/en/sab-23-01_e_.pdf, accessed on 1 June 2018.Search in Google Scholar

[12] OPCW Scientific Advisory Board, Response to the Director-General’s request to the Scientific Advisory Board to provide further advice on scheduled chemicals, Twenty-Third Session, 18–22 April 2016, SAB-23/WP.1 of 28 April 2016. Available to download at https://www.opcw.org/fileadmin/OPCW/SAB/en/sab-23-wp01_e_.pdf, accessed on 1 June 2018.Search in Google Scholar

[13] C. M. Timperley, J. E. Forman, M. Abdollahi, A. S. Al-Amri, I. P. Alonso, et al. Advice on chemical weapons sample stability and storage provided by the Scientific Advisory Board of the Organisation for the Prohibition of Chemical Weapons to increase investigative capabilities worldwide. Talanta188, 808 (2018). (https://doi.org/10.1016/j.talanta.2018.04.022).10.1016/j.talanta.2018.04.022Search in Google Scholar

[14] OPCW Scientific Advisory Board, Report of the Twenty-Second Session held on 8–12 June 2015, SAB-22/1 of 21 July 2015, Annex 2, pp. 27–29. The meeting report is available at https://www.opcw.org/fileadmin/OPCW/SAB/en/sab-22-01_e_.pdf, accessed on 1 June 2018.Search in Google Scholar

[15] For information on IUPAC, see https://iupac.org/, accessed on 1 June 2018.Search in Google Scholar

[16] For information on CAS, see https://www.cas.org/, accessed on 1 June 2018.Search in Google Scholar

[17] The current composition, terms of reference, rules of procedure, and documents of the OPCW SAB can be found at https://www.opcw.org/about-opcw/subsidiary-bodies/scientific-advisory-board/, accessed on 1 June 2018.Search in Google Scholar

[18] A factsheet about the OPCW SAB and its work in 2017 is available online at https://www.opcw.org/fileadmin/OPCW/SAB/en/2017_OPCW_SAB.pdf, accessed 1 June 2018.Search in Google Scholar

[19] For an article by the then OPCW SAB Chairperson, Professor Alejandra Graciela Suárez (of Argentina), on the role and activities of the SAB, refer to OPCW Today3, 6 (2014). https://www.opcw.org/fileadmin/OPCW/OPCW_Today/OPCW_Today_-_Vol_3_No_1.pdf, accessed on 1 June 2018.Search in Google Scholar

[20] A science and diplomacy paper that discusses international science collaboration and mentions the SAB is: B. Maneschi, J. E. Forman, Science & Diplomacy, 4, (2015) http://www.sciencediplomacy.org/perspective/2015/intersection-science-and-chemical-disarmament, accessed on 1 June 2018.Search in Google Scholar

[21] Annex of the OPCW Report of the Scientific Advisory Board on Developments in Science and Technology, RC-2/DG.1, Organisation for the Prohibition of Chemical Weapons, The Hague, 2008, paragraph 3.5. Report available at: https://www.opcw.org/fileadmin/OPCW/CSP/RC-2/en/RC-2_DG.1-EN.pdf, accessed 27 June 2018.Search in Google Scholar

[22] OPCW Report of the Scientific Advisory Board on Developments in Science and Technology for the Third Special Session of the Conference of the States Parties to Review the Operation of the Chemical Weapons Convention, RC-3/DG.1, Organisation for the Prohibition of Chemical Weapons, The Hague, 2012, paragraph 76. The report is available at this address: https://www.opcw.org/fileadmin/OPCW/CSP/RC-3/en/rc3dg01_e_.pdf, accessed 27 June 2018.Search in Google Scholar

[23] A. J. Bell, J. Murrell, C. M. Timperley, P. Watts. J. Am. Soc. Mass Spectrom.12, 902 (2001).10.1016/S1044-0305(01)00274-4Search in Google Scholar

[24] J. D. Barr, A. J. Bell, F. Ferrante, G. La Manna, J. L. Mundy, C. M. Timperley, M. J. Waters, P. Watts. Int. J. Mass Spectrom.244, 29 (2005).10.1016/j.ijms.2005.04.004Search in Google Scholar

[25] A. J. Bell, F. Ferrante, S. E. Hall, V. Mikhailov, D. Mitchell, C. M. Timperley, P. Watts, N. Williams. Int. J. Mass Spectrom.269, 46 (2008).10.1016/j.ijms.2007.09.004Search in Google Scholar

[26] D. H. Ash, S. W. Lemire, S. C. McGrath, L. G. McWilliams, J. R. Barr. J. Anal. Toxicol.32, 44 (2008).10.1093/jat/32.1.44Search in Google Scholar PubMed

[27] E. I. Hamelin, N. D. Schulze, R. C. Shaner, R. M. Coleman, R. J. Lawrence, B. S. Crow, E. M. Jakubowski, R. C. Johnson. Anal. Bioanal. Chem.406, 5195 (2014).10.1007/s00216-014-7702-2Search in Google Scholar PubMed PubMed Central

[28] Z. Nie, Y. Zhang, J. Chen, Y. Lin, B. Wu, Y. Doug, J. Feng, Q. Liu, J. Xie. Anal. Bioanal. Chem.406, 5203 (2014).10.1007/s00216-014-7916-3Search in Google Scholar PubMed

[29] Y. Lin, J. Chen, L. Yan, L. Guo, B. Wu, C. Li, J. Feng, Q. Liu, J. Xie. Anal. Bioanal. Chem.406, 5213 (2014).10.1007/s00216-014-7695-xSearch in Google Scholar PubMed

[30] H. Rice, C. H. Dalton, M. E. Price, S. J. Graham, A. C. Green, J. Jenner, H. J. Groombridge, C. M. Timperley. Proc. Roy. Soc. A471, 20140891 (2015). (http://dx.doi.org/10.1098/rspa.2014.0891).10.1098/rspa.2014.0891Search in Google Scholar PubMed PubMed Central

[31] M. E. Price, C. J. Docx, H. Rice, S. J. Fairhall, S. J. C. Poole, M. Bird, L. Whiley, D. P. Flint, A. C. Green, C. M. Timperley, J. E. H. Tattersall. Toxicol. Lett.244, 154 (2016).10.1016/j.toxlet.2015.08.013Search in Google Scholar PubMed

[32] M. Balali-Mood, R. J. Mathews, R. Pita, P. Rice, J. Romano, H. Thiermann, J. L. Willems. Practical Guide for Medical Management of Chemical Warfare Casualties, International Cooperation and Assistance Division, Assistance and Protection Branch, OPCW, 2016, at https://www.opcw.org/fileadmin/OPCW/ICA/APB/Practical_Guide_for_Medical_Management_of_Chemical_Warfare_Casualties_-_web.pdf, accessed on 1 June 2018.Search in Google Scholar

[33] M. Berglund, M. E. Wiesser. Pure Appl. Chem.83, 397 (2011).10.1351/PAC-REP-10-06-02Search in Google Scholar

[34] J. M. Harrison. J. Labelled Comp. Radiopharm.29, 1175 (1991).10.1002/jlcr.2580291010Search in Google Scholar

[35] J. W. Lown, R. R. Kogarty, A. V. Joshua. J. Org. Chem.47, 2027 (1982).10.1021/jo00132a010Search in Google Scholar

[36] L. Yue, Y. Wei, J. Chen, H. Shi, Q. Liu, Y. Zhang, J. He, L. Guo, T. Zhang, J. Xie, S. Peng. Chem. Res. Toxicol.27, 490 (2014).10.1021/tx4003403Search in Google Scholar PubMed

[37] J. C. Boursnell, G. E. Francis, A. Wormall. Biochem. J.40, 743 (1946).10.1042/bj0400743Search in Google Scholar

[38] T. E. Banks, J. C. Boursnell, G. E. Francis, F. L. Hopwood, A. Wormall. Biochem. J.40, 745 (1946).10.1042/bj0400745Search in Google Scholar

[39] Z. Nie, Q. Liu, J. Xie. Talanta85, 1154 (2011).10.1016/j.talanta.2011.05.041Search in Google Scholar PubMed

[40] A. Fidder, D. Noort, A. L. de Jong, H. C. Trap, L. P. A. de Jong, H. P. Benschop. Chem. Res. Toxicol.9, 788 (1996).10.1021/tx9502150Search in Google Scholar PubMed

[41] C. M. Timperley, R. M. Black, M. Bird, I. Holden, J. L. Mundy, R. W. Read. Phosphorus Sulfur Silicon178, 2027 (2003).10.1080/10426500390228710Search in Google Scholar

[42] S. P. Harvey, L. L. Szafraniec, W. T. Beaudry. US patent 6017750 A 20000125 (2000).Search in Google Scholar

[43] B. Muir, B. J. Slater, D. B. Cooper, C. M. Timperley. J. Chromatogr. A1028, 313 (2004).10.1016/j.chroma.2003.12.001Search in Google Scholar

[44] B. Muir, S. Quick, B. J. Slater, D. B. Cooper, M. C. Moran, C. M. Timperley, W. A. Carrick, C. K. Burnell. J. Chromatogr. A1068, 315 (2005).10.1016/j.chroma.2005.01.094Search in Google Scholar

[45] W. Carrick, L. Fernee, D. Francis. J. Therm. Anal. Calorim.79, 101 (2005).10.1007/s10973-004-0569-2Search in Google Scholar

[46] V. G. Sakharovskii, V. I. Tugushov, E. V. Kasparova, A. M. Zyakun, A. I. Kochergin, A. M. Boronin. Russian J. Appl. Chem.74, 259 (2001).10.1023/A:1012730319196Search in Google Scholar

[47] C. M. Timperley. Best Synthetic Methods – Organophosphorus (V) Chemistry, Elsevier, Oxford, UK, 2015.Search in Google Scholar

[48] J. L. Mundy, J. M. Harrison, P. Watts, C. M. Timperley. Phosphorus Sulfur Silicon181, 1847 (2006).10.1080/10426500500543008Search in Google Scholar

[49] D. G. Ott, M. J. Reisfeld, T. W. Whaley. Synth. Appl. Isot. Labelled Compd. Proc. Int. Symp. 2nd 409 (1986).Search in Google Scholar

[50] A. W. A. D. McNaught (Ed.). Compendium of Chemical Terminology, Second Edition, IUPAC, Blackwell Scientific Publications, Oxford, UK, 1997.Search in Google Scholar

[51] A. J. Ooms, H. L. Boter. Biochem. Pharmacol.14, 1839 (1965).10.1016/0006-2952(65)90274-1Search in Google Scholar

[52] S. P. Harvey, J. E. Kolakowski, T. C. Cheng, V. K. Rastogi, L. P. Reiff, J. J. DeFrank, F. M. Raushel, C. Hill. Enzyme Microb. Technol.37, 547 (2005).10.1016/j.enzmictec.2005.04.004Search in Google Scholar

[53] D. B. Cooper, J. M. Harrison, T. D. Inch. Tetrahedron Lett.31, 2697 (1974).10.1016/S0040-4039(01)92333-0Search in Google Scholar

[54] H. E. T. Spruit, H. C. Trap, J. P. Langenberg, H. P. Benschop. J. Anal. Toxicol.25, 57 (2001).10.1093/jat/25.1.57Search in Google Scholar PubMed

[55] Z. Miao, H. Li, Y. Zhou, R. Feng, G. Li. Junshi Yixue Kexnuynan Yuankan23, 205 (1999).Search in Google Scholar

[56] J. R. Smith, J. J. Schlager. J. High Res. Chromatogr.19, 151 (1996).10.1002/jhrc.1240190306Search in Google Scholar

[57] G. R. Van den Berg, D. H. J. M. Platenberg, H. P. Benschop. Rec. Trav. Chim. Pays-Bas91, 929 (1972).10.1002/recl.19720910807Search in Google Scholar

[58] H. L. Boter, A. J. J. Ooms, G. R. van der Berg, C. van Dijk. Rec. Trav. Chim. Pays-Bas85, 147 (1966).10.1002/recl.19660850206Search in Google Scholar

[59] M. Rehavi, S. Maayani, M. Sokolovsky. Life Sci.21, 1293 (1977).10.1016/0024-3205(77)90010-8Search in Google Scholar

[60] A. Meyerhöffer. J. Med. Chem.15, 994 (1972).10.1021/jm00279a030Search in Google Scholar

[61] P. Mahaffy, J. E. Forman, A. W. M. Hay, C. M. Timperley. Chemical safety and security in a rapidly changing world, in Chemistry International38, 38–39 (November-December 2016) (doi:10.1515/ci-2016-0637).10.1515/ci-2016-0637Search in Google Scholar

[62] More information on the OPCW “Science for Diplomats” initiative, and various presentations and materials from these events, can be downloaded at https://www.opcw.org/special-sections/science-technology/science-for-diplomats/, accessed on 1 June 2018.Search in Google Scholar

[63] The “Science for Diplomats” presentation by Dr. Jonathan E. Forman on “Isotopic labels, stereoisomers, & scheduled chemicals – why does this matter? A review of the SAB’s advice”, given on 13 July 2016 to an audience of representatives from States Parties, appears at https://www.opcw.org/fileadmin/OPCW/Science_Technology/Diplomats_Programme/20160713-SciDiplomats-Presentation.pdf, accessed on 1 June 2018.Search in Google Scholar

[64] Information describing the UK Chemical Weapons Act 1996 and its provisions can be found at https://www.legislation.gov.uk/ukpga/1996/6/contents, accessed on 1 June 2018.Search in Google Scholar

[65] Guidance produced by the UK National Authority for those producing, processing, consuming, importing or exporting chemicals covered by the CWC is provided at this web address: https://www.gov.uk/guidance/chemical-weapons-convention-guidance, accessed on 1 June 2018.Search in Google Scholar

[66] Report of the Scientific Advisory Board on Developments in Science and Technology for the Fourth Special Session of the Conference of the States Parties to Review the Operation of the Chemical Weapons Convention, OPCW Review Conference, Fourth Session on 21–30 November 2018, RC-4/DG.1 of 30 April 2018, paragraph 24. To download, visit https://www.opcw.org/fileadmin/OPCW/CSP/RC-4/en/rc4dg01_e_.pdf, accessed on 9 May 2018.Search in Google Scholar

[67] G. W. Parshall, G. S. Pearson, T. D. Inch, E. D. Becker. Pure Appl. Chem.74, 2323 (2002).10.1351/pac200274122323Search in Google Scholar

[68] M. Balali-Mood, P. S. Steyn, L. K. Sydnes, R. Trapp. Pure Appl. Chem.80, 175 (2008).10.1351/pac200880010175Search in Google Scholar

[69] K. Smallwood, R. Trapp, R. Mathews, B. Schmidt, L. K. Sydnes. Pure Appl. Chem.85, 851 (2013).10.1351/PAC-REP-12-11-18Search in Google Scholar

[70] OPCW Note by the Technical Secretariat: Summary of the Report on Activities Carried Out in Support of a Request for Technical Assistance by the United Kingdom of Great Britain and Northern Ireland (Technical Assistance Visit TAV/02/18), S/1612/2018 of 12 April 2018. The note is available at https://www.opcw.org/fileadmin/OPCW/S_series/2018/en/s-1612-2018_e___1_.pdf, accessed on 15 July 2018.Search in Google Scholar

[71] See for example: OPCW Statement by the Delegation of Guatemala at the Fifty-Seventh Meeting of the Executive Council, EC-M-57/NAT.13 of 4 April 2018. The statement is available at https://www.opcw.org/fileadmin/OPCW/EC/M-57/en/ecm57nat13_e_.pdf, accessed on 15 July 2018.Search in Google Scholar

[72] The press release on the signing of the IUPAC-OPCW MoU appears at https://www.opcw.org/news/article/opcw-and-international-union-of-pure-and-applied-chemistry-take-partnership-to-new-level/ and the signed MoU document at https://www.opcw.org/fileadmin/OPCW/Industry/OPCW_IUPAC_Signed_MoU_01Dec2016.pdf, accessed on 1 June 2018.Search in Google Scholar

[73] Details of this nomination and the OPCW-The Hague Award can be found at https://www.opcw.org/news/article/recipients-of-the-second-annual-opcw-the-hague-award-announced/, accessed on 1 June 2018.Search in Google Scholar

[74] OPCW Scientific Advisory Board, “Saxitoxin Fact Sheet”, Twenty-First Session, 23–27 June 2014, SAB-21/WP.4 of 28 February 2014. This fact sheet can be downloaded from https://www.opcw.org/fileadmin/OPCW/SAB/en/sab-21-wp04_e_.pdf, accessed on 1 June 2018.Search in Google Scholar

[75] OPCW Scientific Advisory Board, “Ricin Fact Sheet”, Twenty-First Session, 23–27 June 2014, SAB-21/WP.5 of 28 February 2014. This fact sheet can be downloaded from https://www.opcw.org/fileadmin/OPCW/SAB/en/sab-21-wp05_e_.pdf, accessed on 1 June 2018.Search in Google Scholar

[76] M. P. Maidment, S. K. Patel, D. G. Upshall, C. M. Timperley. J. Appl. Toxicol.19, 113 (1999).10.1002/(SICI)1099-1263(199903/04)19:2<113::AID-JAT551>3.0.CO;2-YSearch in Google Scholar

[77] C. M. Timperley. J. Fluorine Chem.94, 37 (1999).10.1016/S0022-1139(98)00343-1Search in Google Scholar

[78] C. M. Timperley. J. Fluorine Chem.125, 685 (2004).10.1016/j.jfluchem.2003.11.021Search in Google Scholar

[79] C. M. Timperley. J. Fluorine Chem.125, 1265 (2004).10.1016/j.jfluchem.2004.02.009Search in Google Scholar

[80] C. M. Timperley, M. J. Waters, J. A. Greenall. J. Fluorine Chem.127, 249 (2006).10.1016/j.jfluchem.2005.11.008Search in Google Scholar

Published Online: 2018-09-19
Published in Print: 2018-10-25

©2018 IUPAC & De Gruyter. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. For more information, please visit: http://creativecommons.org/licenses/by-nc-nd/4.0/

Downloaded on 2.3.2024 from https://www.degruyter.com/document/doi/10.1515/pac-2018-0803/html
Scroll to top button