Evidence for the efficacy of the emetic PP796 in paraquat SL20 formulations – a narrative review of published and unpublished evidence

Abstract

Background

The bipyridyl herbicide paraquat was first introduced into agriculture in the 1960s by Imperial Chemical Industries. Due to issues with unintentional poisoning, the centrally acting emetic PP796 was added in 1976 to the company’s 20% paraquat ion soluble liquid (SL20) formulations (Gramoxone^®) at a concentration of 0.5 g/L or 0.05% (equivalent to 0.071 mg/kg in a 70 kg adult ingesting a minimum lethal dose of 10 mL) to induce early vomiting (within 30 min), reduce paraquat absorption from the gut, and prevent deaths. Its presence in paraquat products was subsequently mandated by the Food and Agriculture Organization Committee of Experts on Pesticides in Agriculture (predecessor to the current FAO/WHO Joint Meeting on Pesticide Specifications). However, no primary pre-clinical or clinical data have been published regarding the effectiveness of PP796. We reviewed the published literature and unpublished company reports for data on the effectiveness of PP796.

Methods

PubMed and Google were searched for published studies on the emetic using the search terms “paraquat” and [“emetic” or “PP796”]. Company documents reporting pre-clinical and clinical studies were accessed at the website of U.S. Right to Know (https://usrtk.org/pesticides/paraquat-papers/). Primary study reports were sought as well as overviews written by company toxicologists.

Results

Pre-clinical dog and monkey studies indicated that the PP796 EC50 dose for vomiting was around 0.5–2 mg/kg. Further increasing the PP796 concentration speeded up the time to first vomit and reduced the amount of paraquat absorbed (as assessed by the 0–24 h plasma area-under-the-curve) 100-fold compared to a control group receiving no PP796. However, the dose selected for paraquat SL20 formulations by the company (0.5 g/L or 0.05%) was based exclusively on a phase II study in the early 1970s involving five volunteers receiving 3 different doses, with only two individuals actually vomiting, supplemented by data from 37 patients taking 2 mg in clinical trials. A UK-mandated toxicovigilance study in the 1980s identified only 21 patients ingesting paraquat SL20 with PP796 for whom data on time to vomit was available; of these patients, 11 vomited within 30 min (52.4%, 95%CI 31–73.7%). No effect on mortality could be identified from any study of paraquat SL containing 0.05% PP796. A clinical study in Sri Lanka 30 years after the emetic was first introduced, of a revised formulation (Gramoxone^® Inteon) containing a three-fold higher amount of PP796, as well as MgSO4 and an alginate, showed increased rates of early vomiting and modestly reduced mortality for patients ingesting up to 100 mL.

Conclusion

Pre-clinical studies showed a clear dose response for PP796 to cause early vomiting, with effective doses in the 0.5–20 mg/kg range. A too low concentration of PP796 was selected for paraquat formulations based on an inadequate phase II study. Currently, evidence that PP796 at 0.05% in paraquat SL20 causes more rapid vomiting after ingestion is weak or unpublished; no evidence of clinical benefit or fewer deaths has been identified. There is no evidence to support the FAO/WHO Joint Meeting on Pesticide Specifications mandate to include PP796 or any other emetic in paraquat products. Products with higher emetic concentrations have been developed but are not widely used; it is possible they may prevent deaths.

Keywords:

• Paraquat
• emetic
• PP796
• poisoning
• formulations

Acknowledgements

I am grateful to Nick Bateman, David Gunnell, Nick Buckley, Martin Wilks, Leah Utyasheva, Mark Davis and the reviewers for their critical comments on the document and to Dr M D Müller, of FAO/WHO JMPS, for his critique on that aspect of the document.

Disclosure statement

ME is a WHO member of the FAO/WHO Joint Meeting on Pesticide Management (JMPM). He received an unrestricted research grant from Cheminova (2012) and travel expenses from Syngenta to attend meetings for the first Inteon study (2005–2006), but no personal income. He wrote a scientific expert report on these documents for PublicEye and Unearthed/Greenpeace, for which he was not paid.

Box 1 Current FAO/WHO JMPS specifications for paraquat dichloride soluble concentrate [21].

Description

“The material shall consist of technical paraquat dichloride, complying with the requirements of FAO Specification 56.302/TK (October 2021), in the form of an aqueous solution (Notes 1 and 2), together with any other necessary formulants, and must contain an effective emetic (Note 3). The material may also include colorants, olfactory alerting agents and thickeners. It shall contain not more than a trace of suspended matter, immiscible solvents and sediment.

“Note 3. An effective emetic, having the following characteristics, must be incorporated into the SL.

• It must be rapidly absorbed (more rapidly than paraquat) and be quick acting. Emesis must occur in about half an hour in at least 50% of cases.

• It must be an effective (strong) stimulant of the emetic centre of the brain, to produce effective emesis. The emetic effect should have a limited ‘action period’, of about 2–3 h, to allow effective treatment of poisoning.

• It must act centrally on the emetic centre in the brain.

• It must not be a gastric irritant because, as paraquat is itself an irritant, this could potentiate the toxicity of paraquat.

• It must be toxicologically acceptable. It must have a short half-life in the body (to comply with the need for a limited action period).

• It must be compatible with, and stable in, the paraquat formulation and not affect the herbicidal efficacy or occupational use of the product.

“The paraquat TK, SL and SG produced by the manufacturer mentioned in the evaluation reports 56.302/2003, 56.302/2020 and 56.302/2021 contain the emetic 2-amino-4,5-dihydro-6-methyl-4-propyl-s-triazole-(1,5-a)pyrimidin-5-one (PP796). The method for determination of PP796 content in TK and formulated products is provided in Appendix 1.

A previous version was more explicit about the need to use PP796: “To date, the only compound found to meet these requirements is 2-amino-4,5-dihydro-6-methyl-4-propyl-s-triazole-(1,5a)pyrimidin-5-one (PP796). PP796 must be present in the SL at not less than 0.23% of the paraquation content” [20].

Additional information

Funding

The Centre for Pesticide Suicide Prevention is funded by a grant from Open Philanthropy, at the recommendation of GiveWell.