UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

MEMORANDUM 

Date: 12/15/2015 

SUBJECT: Strychnine. Human Health Assessment Scoping Document in Support of 

Registration Review 

FROM: 

THROUGH: 

TO: 

PC Code: 076901 

Decision No.: 508056 

Petition No.: NA 

Risk Assessment Type: NA 

TXRNo.: NA 

MRIDNo.: NA 

DP Barcode: D428699 

Registration No.: RegRev-3 133-1 

Regulatory Action: Registration Review 

Case No.: 31 13 

CAS No.: 57-24-9 

40 CFR: NA 

Jaime D' Agostino, Ph.D., Toxicologist 

Matthew Crowley, Biologist ~~::_....A&..L.>-A 

Risk Assessmenr Branch li 

Health Effects Division (7509P) 

Office of Pesticide Programs 

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Jess Rowland, Deputy Division Director ~Q-..:::lo

Jeff Dawson, Acting Deputy Division Director 

Health Effects Division (7509P) 

Office of Pesticide Programs 

Susan Bartow, Chemical Review Manager 

Cathryn Britton, Team Leader 

Kevin Costello, Acting Branch Chief 

Risk Management and Implementation Branch IV 

Pesticide Re-Evaluation Division (7508P) 

Office of Pesti cide Programs 

Attached is the Health Effects Division's (HED) human health risk assessment scoping document for 

strychnine to support Registration Review. 

Page 1 of 11 
Executive Summary 

The Health Effects Division (HED) strychnine Registration Review Team has eva luated the 

database and the most recent human health risk assessment for strychni ne. HEO performed this 

evaluation in order to determine the scope of work necessary to support the existing registrations 

during registration review. The primary source of information for this evaluation was the most 

recent HED chapter of the Reregistratio n Eligibility Decision (RED) document (J. Smith; 

1/22/ 1996). 

Strychnine is·a rodenticide that was first registered for no n-food uses in the U.S. in 1947. 

Strychnine is a terpene indole alkaloid which acts as a convulsant by antagoni zing glycine 

receptors. Glycine is an important inhibitory transmitter to motor neurons. Strychnine is 

currently formulated as a 0.5% grain-based bait or granule applied underground to control 

gophers in pastures, rangeland, cropland, irrigation ditches/canals, and home lawns. Based on 

label descriptions, application can be by spoons, cups, hand probe dispensers, mechanical burrow 

builders, and hand dispersal. Some but not all products are restricted-use. There is also a special 

local need (SLN) registration in Nevada for control of yellow-bellied marmots and gro und 

squirrels in addition to pocket gophers that is a 3.2% paste restricted use product (RUP). 

The toxicology database for strychnine is considered adequate for risk assessment except fo r the 

requirement of an inhalation toxicity study as determined by l-IED's Hazard and Science Policy 

Council (TXR#0057269; J. Leshin). However, label changes (i.e., use of respirators for some 

scenarios), if agreed to by the registrant, could alleviate the need for the study as described in the 

HASPOC document. HED's HASPOC also determined that a repeat dose dermal toxicity study, 

prenatal developmenta l studies (rat and rabbit), a 2-generation reproduction study, an acute 

neurotoxicity battery, a subchronic neurotoxicity battery, an immunotoxicity study, and the 

genotoxicity battery of studi es are not required for strychnine (TXR#0057269; J. Leshin). In the 

1996 RED (J. Smith; 1/2211996), due to the non-food use profile, Points ofDepartures (PODs) 

and toxicity endpoints of concern were not established; however, HED will reassess the need for 

PODs and toxicity endpoints of concern during Registration Review. 

Strychnine is a potent acute toxicant resulting in clinical signs related to neurotoxic ity and 

mortality following acute oral, ocular, and inhalation exposures. In contrast, no toxicity is 

observed following acute dermal exposure to very high doses of strychnine, likely due to low 

dermal absorption. Limited data is available for re peat dose exposure to strychnine due to its 

potent acute toxicity. 

Strychnine is a non-food use rodenticide and its limited and targeted underground uses do not 

warrant estimation of concentrations in drinking water; therefore, a dietary exposure assessment 

is not applicable. 

Strychnine products are intended for use in underground burrows on home lawns, but require 

certain clothing and/or personal protecti ve equipment (PPE) to be worn (long sleeve shirt, pants, 

gloves, and for some products, a respirator). A residential handl er assessment will not be 

conducted for Registration Review because standard HED assumptions for residentiaUconsumer 

applicator specific assessments, such as wearing shorts and a t-shirt without PPE like chemicalPage 2 of 11 
resistant gloves or respirators, would represent non-compliance with current strychnine products. 

If products containing strychnine are meant to be marketed towards and performed by 

consumers/homeowners, HED recommends that label requirements for clothing and/or PPE be 

reevaluated or separate consumer-specific labels be developed and a separate residential handler 

assessment using standard HED assumptions be conducted to evaluate such products. A postapplication residential exposure assessment will also not be conducted due to its underground 

use. Additionally, neither exposure via drift or volatilization is expected due to its formulation 

as solids/pastes and its underground use. 

During Registration Review, HED will conduct a quantitative risk assessment for occupational 

handler inhalation exposure. The occupational exposure database is adequate to support 

Registration Review of strychnine with the use of surrogate datasets for non-standard application 

scenarios. Furthermore, an objective of Registration Review will be to reconcile handler work 

attire and PPE with corresponding end-use acute toxicity-based requirements and potential 

requirements based on the Registration Review occupational handler risk assessment due to the 

varying requirements for work clothing and PPE on product labels. No post-application 

exposure assessment will be conducted as contact with residues following application is not 

anticipated based on the product formulations and underground use. 

Introduction 

Strychnine is a rodenticide that was first registered for non-food uses in the U.S. in 1947. 

Strychnine is a terpene indole alkaloid which acts as a convulsant by antagonizing glycine 

receptors. Glycine is an important inhibitory transmitter to motor neurons. Strychnine was also 

used as a therapeutic agent in humans between the 16th and mid-20th century but no longer has 

any medical uses. 

The Health Effects Division (HED) evaluated the most recent HED chapter of the Reregistration 

Eligibility Decision (RED) document (J. Smith; 1/22/ 1996) for strychnine in association with 

updates to its toxicity, exposure, and usage databases to determine if suffi cient data are available, 

and if further updates are needed, to support Registration Review. 

The structure and chemical names can be found in the chemical identity table in Attachment 1. 

Hazard ldentificationrroxicology 

While no mechanism of action studies were submitted for strychnine, the mechanism for 

mammalian toxicity is well known for this compound based on its previous medical uses and a 

significant body of literature. Please see the U.S. Department of Agriculture (USDA) Forestry 

Services human health and ecological risk assessment for strychnine (P.R. Durkin, 201 0) for a 

comprehensive list of references for the proposed mechanism of action of strychnine. The 

following is a brief summary based on the information presented in that document. Strychnine 

acts as an antagonist for glycine receptors, which is a ligand-gated chloride channel in neurons. 

Glycine is a neurotransmitter critical to the normal function of the nervous system. When 

glycine binds to the glycine receptor on neurons it increases the flow of chloride ions into motor 

neurons which results in inhibition of motor neuron activity. In contrast, binding of strychnine to 

Page 3 ofll 
chloride channels does not result in an increased flow of chloride ions and interferes with the 

normal inhibitory function of glycine. The net result is that strychnine leads to hyper excitability 

by preventing glycine from inhibiting the activity of the motor neurons. At very low doses, 

strychnine acts as a stimulant or performance enhancer, however at higher doses this leads to 

spastic muscl e contracti ons, resulting in death by asphyxiation. 

The toxicology database for stryclmine consists of only the acute six pack studies for the 

technical compound and its formulations. However, there is a significant body ofliterature on 

the toxicity of strychnine based on its medical uses, accidental or suicidal human poisonings, and 

experimental studies in mammals. This body of literature was recently reviewed and 

summarized as part of the USDA Forestry Services human health and ecological risk assessment 

for strychnine (P.R. Durkin, 20 10) and these studi es were considered in the hazard 

characterization of strychnine. HED's Hazard and Science Policy Council (HASPOC) 

determined that a repeat dose dermal toxicity study, prenatal developmenta l studies (rat and 

rabbit), a 2-generation reproduction study, an acute neurotoxicity battery, a subchronic 

neurotoxicity battery, an immunotoxicity study, and the genotoxicity battery of studies are not 

required for strychnine (TXR#0057269; J. Leshin). However, HED's HASPOC decided that an 

inhalation study is required unless the registrant agrees to label changes (i.e., use of respirators 

for some scenarios) developed and incorporated into current labels which would reduce 

inhalation exposures to a point where the margins of exposure (MOEs) based on the HASPOC 

screening criteria would no longer be of concern. The toxicology database for strychnine is 

considered adequate for risk assessment, except for a required inhalation study, based on the 

significant body of literature available and the acute six pack studies. 

The primary toxicity of strychnine is manifested as acute effects due to the potent toxicity of the 

chemical. This included potent acute toxicity following oral, ocular, and inhalation exposure. 

The primary effects observed were clinical signs consistent with neurotoxic effects (such as 

tremors) or mortality. In contrast, strychnine does not appear to be acutely toxic by the dermal 

route. No irritation, mortality, or signs of toxicity were observed in the acute rabbit dermal 

lethality study with technical strychnine up to a dose of2000 mg/kg. This is likely due to a very 

low dermal absorption of strychnine. While no direct measurement of the dennal absorption for 

strychnine is available, a dermal absorption value of 0.25% over an 8 hour period with a dermal 

load of 1 J..Lg/cm2 was estimated using the National Institute for Occupational Health and Safety 

(NIOSH) finite dose skin permeation calculator 

(http://www.cdc.gov/niosh/topics/skin/finiteSkinPermCalc.html) which predicts a chemical 's 

dermal absorption based on its physical chemistry parameters. 

There is limited data on the repeat dose toxicity of strychnine due to the potent acute toxicity 

observed. For example, one study in the literature set out to determine a maximally tolerated 

dose of strychnine in rats following gavage dosing (Seidl and Zbinden, 1982). Consistent with 

the LDso values determined in the guideline acute lethality study, some number of the rats in 

each sex died at these doses showing tonic muscle contractions and respiratory paralysis. The 

animals that survived showed increased muscle tone or a slight tremor 10 to 20 minutes 

following dosing that resolved within 60 minutes. 

Page 4 of 11 
In 1996, because of the severe oral toxicity of this chemical and the nonfood use status, risk 

assessments were not conducted (J. Smith; 1/22/1996). Since l-IED plans to perform a 

quantitative occupational inhalation exposure assessment during Registration Review, an 

inhalation endpoint will be chosen during Registration Review. No other endpoints are 

anticipated to be needed as there is no anticipated exposure to children, there is no dietary 

exposure, and the combination of the estimated low dermal absorption and the lack of acute 

detmal toxicity supports that a quantitative dermal occupational dermal assessment is not 

needed. The acute toxicity profile of strychnine is summarized in Attachment 2. 

Conclusions for Hazard Identification/Toxicology 

The toxicity database is adequate for the purpose of registration review, except for the lack of an 

inhalation study which is required at this time. During Registration Review, HED will select an 

inhalation endpoint for use in occupational risk assessments. 

Residue Chemistry and Dietary Exposure 

Strychnine is a non-food use rodenticide and its limited and targeted underground uses do not 

warrant estimation of concentrations in drinking water; therefore, a dietary exposure assessment 

is not applicable. 

Conclusions for Residue Chemistry and Dietary Exposure 

HED does not anticipate conducting a dietary risk assessment during Registration Review. 

Residential Exposure 

Strychnine products are intended for use in underground burrows on home lawns, but require 

cet1ain clothing and/or personal protective equipment (PPE) to be worn (long sleeve shirt, pants, 

gloves, and, for some products, a respirator). A residential handler assessment will not be 

conducted for Registration Review because standard HED assumptions for residential/consumer 

applicator specific assessments, such as wearing shorts and at-shirt without PPE like chemicalresistant gloves or respirators, would represent non-compliance with current strychnine products. 

An exposure assessment for occupational handlers/applicators assuming compliance with label 

requirements for work clothing and/or PPE wi ll be conducted. If products containing strychnine 

are meant to be marketed towards and performed by consumers/homeowners, HED recommends 

that label requirements for clothing and/or PPE be reevaluated or separate consumer-specific 

labels be developed and a separate residential handler assessment using standard l-IED 

assumptions (consumer applicators will wear just shorts and a short-sleeve shirt) be conducted to 

evaluate such products. 

Additionally, a residential post-application exposure assessment will not be conducted as contact 

with or ingestion of residues is not expected due to the underground nature of the applications. 

Spray Drift and Volatilization 

Page 5 of 11 
Because strychnine is applied as either a granule/bait or paste via hand or hand-operated 

equipment in underground burrows, neither exposure via drift or volatilization is expected. 

Conc lusions for Residential Exposure 

There are strychnine products for use in residential settings in underground gopher burrows of 

home lawns. For Registration Review, however, residential handler assessments will not be 

conducted based on label requirements for clothing and PPE nor will a post-application exposure 

assessment be conducted due to its underground use. Additionally, neither exposure via drift or 

volatilization is expected due to its formulation as solids/pastes and its underground use. 

Occupational Exposure 

Strychnine is currently formulated as a 0.5% grain-based bait or granule and can be applied by 

professional applicators to control gophers in pastures, rangeland, cropland, and home lawns. 

Based on label descriptions, application can be by spoons, cups, hand probe dispensers, 

mechanical burrow builders, and hand dispersal. Some but not all products are restricted-use. 

Products state that approximate ly 1 tablespoon of product should be placed in each 

burrow/tunnel and that 1-3 lbs of product will treat an acre depending on the number of burrows 

(at 0.5% strychnine that is approximately 0.0 15 lb ai/acre). 

There is also a speeiallocal need (SLN) registration in Nevada for control of yellow-bellied 

marmots and ground squirrels in addition to pocket gophers that is a 3.2% paste restricted use 

product (RUP). The label for the SLN paste product instructs users to mix the paste in a large 

plastic bag at a rate of7 fluid ounces of paste per pound of alfalfa or cut vegetables (e.g., carrots 

or parsnip), or approximately 0.0 15 lb strychnine per pound of bait (7 fl oz prod/lb veg bait * 1 

gal/ 128 fl oz * 8.34 lb/gal *3.2% ai). A teaspoon of bait is then placed in the burrows by hand or 

with a long-handled spoon. 

Occupational Handlers 

The most recent HED risk assessment in 1996 did not identify short-, intermediate-, or longterm/chronic toxicological endpoints for strychnine and did not quantitatively assess risk for 

occupational handler exposure. However, the evaluation concluded that there were risks of 

concern for applicators and outlined potential mitigation options inc luding limiting access to and 

use of strychnine end-use products to professional applicators who can be required personal 

protective equipment, including respirators, as we ll as restrictions on powder and paste 

fonnulations. As a result. the 1996 RED required certain PPE requirements based on the product 

fonnulation. 

Currently, requirements for work clothing and PPE vary on product labels. Some only require 

base line work attire (long sleeve shirt, long pants, shoes/socks) with cotton gloves, while others 

require chemical/water-resistant gloves and dust/mist filtering respirators. An objective of 

Registration Review will be to reconcile handler work attire and PPE with corresponding enduse acute toxicity-based requirements and potential requirements based on the Registration 

Review occupational handler risk assessment. 

Page 6 of 11 
Based on the currently registered uses, Registration Review will include an inhalation 

occupational handler exposure assessment only; based on the estimated low dermal absorption 

(0.25% at a dermal loading of 1 f.1g/cm2

) , a dermal exposure assessment will not be conducted. 

Exposures are antic ipated to be short-term only; intem1ediate-term and chronic exposures are not 

expected. The occupational handler assessment should be conducted for the following scenarios: 

• Loading/applying granul es (0.0 15 lb ai/acre) 

o By hand 

o With a spoon or cup 

o With a mechanical burrow builder 

o With a hand probe dispenser 

• Mixing/loading/applying pastes (0.0 15 lb ai/lb vegetables) 

Some of these scenarios arc not standard appli cation scenarios therefore surrogate datasets will 

be used to complete the risk assessment. For mixing/loading and applying via mechanical 

burrow builder, datasets for assessment of tractor-drawn granule spreaders are recommended. 

Assessment of application via hand probe dispenser does not need to be quantified as the 

application is done by the probe underground - exposure during loading of the probe is 

adequately covered by assessment of hand dispersal or spoon or cup application exposure. For 

assessment of exposure during mixing of the paste formulation with vegetable baits, datasets for 

mixing/loading liquid formulations is recommended. 

Occupational Post-application Exposure 

Due to its formulation as a solid or paste and its targeted underground use, no inhalation 

exposure or dermal contact with residues are expected fo llowing applications. Therefore, when 

applicable, restricted entry intervals (REis) will default to the standard active ingredient acute 

toxicity-based requirements. 

Conclusions for Occupational Exposure 

Through use of surrogate datasets, the occupational exposure database is adequate to support 

Registration Review of strychnine. The most recent occupational assessments are not reflective 

of current policies and data, so these assessments should be updated. Occupational handler 

exposure will be quantitatively assessed for the scenarios as outlined above. No post-application 

exposure assessment wi ll be conducted. 

Risk Assessment Updates, Data Deficiencies, and Label Revisions 

The following study is required to support Registration Review of strychnine: 

• An inJ1alation study to address occupational exposure by this route or label changes (i.e., 

use of respirators for some scenarios), that could alleviate the need for the study. Due to 

the high acute toxicity of the compound, a guideline 90-day study is not recommended. 

Instead, a subacute inhalation study that is well designed to identify the key neurotoxic 

Page 7 of 11 
effects (clinical signs) at the critical time of peak effect, in addition to the typical 

evaluations of a guideline inhalation study, is recommended. 

EPA anticipates conducting the following risk assessment updates during Registration Review: 

Toxicology: 

• HED will chose an inhalation endpoint for use in occupational exposure assessments. 

Dietary Exposure: 

• None. 

Occupational/Residential Exposure: 

• HED anticipates conducting a quantitative occupational exposure assessment for 

inhalation exposure for the registered uses. 

Public Health and Pesticide Epidemiology Data 

For this evaluation, the Agency consulted the OPP Incident Data System (IDS), the Centers for 

Disease Control and Prevention/National Institute for Occupational Safety and Health 

(CDC/NIOSH) Sentinel Event Notification System for Occupational Risk-Pesticides (SENSOR), 

and the National Pesticide Information Center (NPIC) databases for pesticide incident data on 

the active ingredient strychnine (D430 176; S. Recore; 11 / 17/20 15) between the period of 1998-

20 11 , which is following implementation of the mitigation recommended in the RED. Based on 

the low frequency and severity of the incidents reported in IDS and SENSOR-Pesticides, there 

does not appear to be a concern that warrants further investigation. Strychillne is not included in 

the Agricultural Health Study (AHS); therefore, that study does not provide information for this 

document. 

Tolerance Assessment and International Harmonization 

There are no tolerances for strychnine as it is a non-food use rodenticide. 

Environmental Justice 

Potential areas of environmental justice concerns, to the extent possible, will be considered in 

Registration Review, in accordance with U.S. Executive Order 12898, "Federal Actions to 

Address Environmental Justice in Minority Populations and Low-Income Populations," 

(http://w\Yw.archives.gov/fcdcra l-rcgistc rh:xcc utive-ordcrs/pdfi'l2898.ptlf). As a part of every 

pesticide risk assessment, OPP considers a large variety of conswner subgroups according to 

well-established procedures. In line with OPP policy, HED estimates risks to pesticide 

exposures that are based on activities in and around the home that involve pesticide use in a 

residential setting. Whenever appropriate, these non-dietary exposures are calculated based on 

home use of pesticide products and associated risks for adult applicators and for toddlers, youths, 

and adults entering or playing on treated areas post-application are evaluated. 

Page 8 of 11 
Cumulative Risk Assessments 

Unlike other pesticides for which EPA has followed a cumul ative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to strychnine and any other substances and strychnine does not appear to produce a toxic 

metabolite produced by other substances. For information regarding EPA's efforts to determine 

which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of 

such chemicals, see the policy statements released by EPA's Office of Pesticide Programs 

concerning common mechanism determinations and procedures for cumulating effects from 

substances found to have a common mechanism on EPA's website at 

http://www.epa.gov/pesticides/cumulative/. 

References 

Author Barcode Date Title 

J. Smith NA 1/22/1996 Strychnine: HED chapter of the reregistration eligibility decision 

document, Case #3133 

J. Lcshin TXR#0057269 NA Strychnine: Summary of Hazard and Science Policy Council 

(HASPOC) Meeting of December 3, 2015: Recommendation on 

the Requirement for a non-food use database of toxicity studies 

P. Durkin NA 3/27/2010 Strychnine Human Health and Ecological Risk Assessment Final 

Report 

S. Recore D430 176 11/17/2015 Strychnine: Tier I (Scoping) Review of Human Incidents and 

Epidemiology 

Seidl and Archives of 1982 Subchronic Oral Toxicity of strychnine in Rats 

Zbinden Toxicology. 51: 

267-271 

Attachments 

Attachment I. Chemical Identity Table for Strychnine 

Attachment 2. Summary of Acute Toxicity Profile for Strychnine for Use in Human Health Risk 

Assessments 

Page 9 of J1 
Attachment 1. Strychnine Chemical Identity. 

Table Al Strychnine Nomenclature. 

Chemical structure fN 

H .. 

'

·· .. 

~ H 

I " ' H 

' N H 0 

H 

0 

Common name Strychnine 

Company experimental None 

name 

IUPAC name strychnidin-1 0-one 

CAS name strychnidin-1 0-one 

CAS registry number 57-24-9 

Page 10 of 11 
Attachment 2. Summary of Acute Toxicity Profile for Stryclmine for Use in Human Health Risk 

Assessments. 

Table A3.1. Acute Toxicity Profile - Strychnine technical 

Guideline Study Type MRID(s) Results Toxicity 

No. Category 

870.1100 Acute oral - rat 40908901 LDso I 

41210701 M = 6.4 mg!kg 

F = 2.2 mg/kg 

870.1200 Acute dermal - rabbit 40908902 LDso > 2000 III 

412 10702 mg/kg 

No signs of 

toxicity 

observed. 

870.1300 Acute inhalation - rat Study not 

submitted 

870.2400 Acute eye irritation - rabbit 4090894 Irritation and I 

41210704 mortality 

870.2500 Acute dermal irritation- 40908903 No irritation, IV rabbit 

410 I 0703 mortality, or 

signs of 

toxicity 

observed 

870.2600 Skin sensitization- guinea Not a sensitizer NA pig 44684601 

Page 11 of 11