UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

 

OFFICE OF PREVENTION, 

 PESTICIDES AND 

TOXIC SUBSTANCES 

 June 25, 2008 

MEMORANDUM 

SUBJECT: Mode of Action, Eye Irritation, and the Intra-Species Factor: Comparison 

of Chloropicrin and MITC 

PC Code: 081501 Chloropicrin 

 068103 MITC 

 039003 Metam Sodium 

 035602 Dazomet 

DP Barcode: DP 293356 

MRID No.: None Registration No.: None 

Petition No.: None Regulatory Action: None 

Assessment Type: Single Chemical/ Nonfood Reregistration Case No.: None 

TXR No.: 0054860 CAS No.: 137-42-8 Metam Sodium, 76-

06-2 chloropicrin, 533-74-4 Dazomet, 556-61-

6 MITC

FROM: Elissa Reaves, Toxicologist 

Reregistration Branch II 

Health Effects Division (7509P) 

Anna Lowit, Toxicologist 

 Toxicology and Epidemiology Branch 

Health Effects Division (7509P) 

 

THRU: Felecia Fort, Branch Chief 

Reregistration Branch II 

Health Effects Division (7509P) 

TO: Karen Santora, Chemical Review Manager 

 Reregistration Branch II 

 Special Review & Reregistration Division (7508P) 

The following document is written in response to recent documents submitted to EPA by 

TERA on behalf of the registrant, AMVAC, and public comments submitted by the 

Metam Sodium Alliance with regard to MITC mode of action and intra-species factor 

This document also clarifies the scientific data which support reduction of the intraspecies factor for chloropicrin. 

Page 1 of 15 
Background:

EPA is undergoing re-registration of several soil fumigants, including metam sodium, 

dazomet, and chloropicrin. Metam sodium and dazomet each degrade soon after 

application to methylisocyante (MITC). Post-application exposure in air to workers and 

by-standers following off-gassing of chloropicrin and MITC are key pathways of 

exposure being considered in the human health risk assessments. This memo provides 

descriptions of important issues for the risk assessment of chloropicrin and MITC such 

as mode of action, eye irritation, and the intra-species factor. 

The Agency has relied on following relevant frameworks and guidance documents in the 

conclusions presented here: 

• Mode of Action Framework as described in U.S. EPA (1999, 2005), SonichMullin et al. (2001), and Meek et al. (2003). This framework, based in large part 

on the Bradford-Hill criteria for determining causality in epidemiology studies, 

describes a framework for evaluating mode of action using animal data. In brief, 

this framework is described by the following steps (extracted from Seed et al, 

2005): 

o Postulated MOA. A brief description of the sequence of measured 

events, starting with chemical administration, to the formation of the toxic 

effect at a given site. 

o Key events. Clear descriptions of each of the key events (measurable 

parameters) that are thought to underlie the MOA. 

o Dose-response relationships. Dose-response relationships identified for 

each key event, and comparisons presented of dose-response 

relationships among key events and with the toxic effect. 

o Temporal association. Sequence of key events over time that lead to the 

toxic effect. This includes any MOA differences specific to different life 

stages. 

o Strength, consistency, and specificity of association of key events and 

the toxic effect. Complete assessment and presentation of the 

relationships among key events, precursor lesions, and the toxic effect, 

portrayal of the consistency of observations across studies of different 

designs. 

o Biological plausibility and coherence. Determination of whether key 

events and the sequence of events are consistent with current biological 

thinking, regarding both the specific toxic effect in general and the 

specific chemical under review. 

o Other MOAs. Alternative MOAs that may be applicable for the chemical 

under review. Comparison of their likelihood vis-`a-vis the proposed 

MOA. 

o Conclusion about the MOA. Overall indication of the level of confidence 

in the postulated MOA. 

o Uncertainties, inconsistencies, and data gaps. Identification of 

information deficiencies in the case; description of inconsistent findings in 

the data at large; evaluation of uncertainties; proposal of pointed 

research that could significantly inform the case. 

Page 2 of 15 
• IPSC (International Programme on Chemical Safety) Guidance on Chemical 

Specific Adjustment Factors (CSAFs, 2005). In 2005, the WHO published its 

guidance for deriving chemical specific adjustment factors (CSAFs). This CSAF 

guidance describes approaches for use of kinetic and mechanistic data to refine 

inter-species and intra-species extrapolation factors. The IPSC guidance is 

based in large part on analyses by Renwick (1993) and Renwick and Lazarus 

(1998) which describe the use of toxicokinetic and toxicodynamic data as a 

means of replacing the traditional 10-fold safety factors for human sensitivity and 

experimental animal-to-human extrapolation. Although EPA does not yet have 

guidance for developing CSAFs, also often called data-derived 

extrapolation/uncertainty factors (DDEFs), the Agency has used these concepts 

in some risk assessments. Understanding mode of action is an important 

component of deriving CSAFs in that mode of action provides the foundation for 

understanding what toxicokinetic and/or toxicodynamic characteristics are critical 

for evaluating inter- or intra-species extrapolation. 

The first part of this memo includes a comparison of the toxicology databases (both 

animal and human) for chloropicrin and MITC. This is followed by a description of the 

chloropicrin mode of action and toxicology data along with the scientific support for 

reducing the intra-species factor. The third section of the memo describes the 

deficiencies in the MITC database which precludes the refinement of the intra-species 

factor and discusses in general what information would need to be available prior to any 

consideration of deriving a CSAF, or DDEF, for MITC with regard to intra-species 

extrapolation. 

I. Comparison of Chloropicrin and MITC Toxicology Databases 

The animal database for chloropicrin is robust and especially provides insight into the 

dose-response, temporal concordance, and progression of respiratory irritation from 

varying concentrations of chloropicrin. Specifically, the inhalation database consists of 

durations ranging from 30 minutes to two years (108 weeks) and evaluates acute, 

subchronic, chronic/cancer, reproductive and developmental toxicity. From these rodent 

studies, it is apparent that factors such as air concentrations of chloropicrin and duration 

of exposure are important in the development of port-of-entry effects. Chloropicrin is 

also a known sensory irritant with a defined mode of action. 

An intentional dosing human sensory irritation study is available for chloropicrin. The 

human study was evaluated by the Human Studies Review Board (HSRB) in June, 

2006. The HSRB concluded that the chloropicrin human study was scientifically sound 

for the purpose of estimating a safe level of inhalation exposure to chloropicrin (HSRB 

Final Report, October 2006; 

http://www.epa.gov/osa/hsrb/files/june2006mtgreportfinal100606). The chloropicrin 

study is a controlled three phase human irritation study that provides information on: 1) 

the odor threshold for chloropicrin; 2) the detection of feel in healthy subjects’ eyes, 

nose, and throat; 3) the irritation potential from repeated exposures; and 4) the 

magnitude of variability in subjects’ responses to varying concentrations and durations of 

exposure to chloropicrin. The concentrations (50 ppb to 1200 ppb) and durations (1-2 

seconds to 60 minutes/day for 4 consecutive days) of exposure to chloropicrin varied 

with each phase of the study. The human irritation study provides concentrations of 

chloropicrin that are recognized as irritation to eyes but not in the nose or throat and 

Page 3 of 15 
before irritation of the respiratory system. Since recognition of irritation in rodents is 

obviously not possible, the human study provides critical information regarding the 

recognition of irritation before physical irritation is present. Phase 2 and 3 in the human 

study evaluated chloropicrin concentrations (0.05 ppm to 0.15 ppm) orders of magnitude 

below concentrations that produced port-of-entry effects after acute (10.6 ppm), 

subchronic (1.0 ppm) and chronic (0.5 ppm) exposure in the rodent studies. 

The inhalation database of toxicology studies which support the MITC hazard 

characterization and hazard identification are more limited compared with chloropicrin 

(Table 1). The inhalation database for metam sodium consists of one subchronic 

inhalation study. However, there are two subchronic inhalation studies for MITC as well 

as an eye irritation and odor threshold goggle study in human subjects with MITC. 

Table 1. Comparison of animal and human data for MITC and chloropicrin, 

MITC Chloropicrin 

Animal 

Using toxicity information from MITC, metam 

sodium, metam potassium, dazomet to bridge 

among chemicals for the oral route 

No bridging to other fumigants 

Limited temporal and dose-response data (only 

from acute lethality studies) 

Temporal data from minutes to years in animals 

and seconds to minutes in humans 

Doses/concentrations from 100 ppb to 11 ppm 

Incomplete animal database via inhalation 

-one subchronic inhalation (metam sodium) 

-two subchronic inhalation & acute lethality 

(MITC) 

Robust animal database via inhalation 

- acute (including RD50) 

- subchronic 

- developmental & reproduction (rat & rabbit) 

- reproductive 

- chronic/cancer 

-mutagenicity 

No data to determine susceptibility Developmental and reproduction data demonstrate 

no susceptibility 

Data comparing local vs. systemic data are 

incomplete 

Robust local vs. systemic data 

- good port of entry information (local)—eye 

recognition and severity eye irritation scores in 

humans, nose and respiratory parameters 

-good identification of systemic effects—body 

weight loss at high concentrations in animals 

Human

Human Goggle Study Human Inhalation Study (Chamber) 

Eyes only; No nose, throat, respiratory 

parameters, physiological parameters 

Eyes, nose, throat, respiratory, physiological 

parameters 

Page 4 of 15 
No data to evaluate relative sensitivity of eyes 

to other targets 

Eyes the most sensitive target, 

No severe eye, nose, or respiratory irritation at 150 

ppb for one hour/day for 4 consecutive days 

-eye recognition at 100 ppb (40-60 minutes) and 

150 ppb (20-30 minutes) 

Don’t know day to day carry over effects, not 

examined in human study 

Identified no day to day carry over effects, each day 

a new day 

I. Chloropicrin: Mode of action and Intra-species factor 

A. Mode of Action 

The first step in consideration of refinement of uncertainty factors is the characterization 

of the mode of action. The mode of action framework, based in large part on the 

Bradford-Hill criteria for determining causality in epidemiology studies, describes a 9 

step framework for evaluating mode of action using animal data. For chloropicrin, the 

mode of action is sensory irritation, a well documented mode of action. As a sensory 

irritant, chloropicrin stimulates the trigeminal nerve which mediates sensations in the 

nose, eyes, throat, and upper respiratory tract. As such, chloropicrin is detected at 

concentrations that are lower than would be expected to result in port-of-entry related 

toxic effects (Alarie, 1973, Buckley et al., 1984, Shusterman 2002). Responses from a 

sensory irritant are distinct from that of chemical stimulation (specialized olfactory or 

taste receptor cells). Irritation responses from a sensory irritant may include localized 

and transient chemosensations such as burning, itching, and stinging, as well as 

associated physiologic (e.g., secretory) responses resulting from surrounding tissues 

(e.g., eyelid closure, inflammation, etc.). This is a local surface reactivity type of effect 

which is distinctly different from a systemic type of effect. The parent compound is the 

key stimulant of the trigeminal nerve and metabolism is not required to produce the 

irritation response. 

1. Key events: Both the rodent database and human study for chloropicrin 

supports the key events in sensory irritation as the mode of action. 

Figure 1 below outlines the key events of chloropicrin. Acute air or 

external exposure to chloropicrin will produce sensations in the eyes 

through the triggering of the trigeminal nerve. Triggering of the trigeminal 

nerve is a surface reaction from air concentrations such that an internal 

dose is not required for the chemosensation. Triggering of the trigeminal 

nerve was evident in the chloropicrin human study (MRID 46443801) and 

quantification of the chemosensations from sensory irritants like that 

produced from chloropicrin vapor has been determined in mice (RD50

concentration) (Hoffman et al., 1999; MRID 451178901; Buckley et al., 

1984). 

Page 5 of 15 
Figure 1. Key events in the MOA of chloropicrin 

Acute Air Chloropicrin Exposure 

↓

Trigeminal Nerve Stimulation 

↓

Eye Detection (Feeling) 

↓

Eye Irritation 

 

2. Dose-Response: Table 2 below highlights the dose-response relationship 

of the key events highlighted in Figure 1. From this table it is apparent 

that concentration and duration of exposure are important in the toxicity of 

the target tissue, onset of effect, and severity of the irritation. As the 

concentration increases the severity of the port-of-entry effect also 

increases. Acutely, eye effects are more sensitive than nose (>12x) or 

lung (>100x). 

Page 6 of 15 
Table 2. Dose-response and temporal concordance of key events from chloropicrin exposure

Key Event NOAEL LOAEL Timing Reference 

Eye 

Recognition 

Human 

300 ppb 

EC50 242 ppb 

seconds 

25 seconds ACGIH 2001 

MRID 46443801 

Eye 

Recognition 73 ppb 

Human 

150 ppb, no eye or 

respiratory irritation 

20-30 minutes MRID 46443801 

Odor 

Recognition 

Human 

EC50 406 ppb 

Median 356 ppb 

1 second MRID 46443801 

Nasal 

Pungency 

Human 

No EC50 or median 

> 1200 ppb 

7 seconds MRID 46443801 

Respiratory 

Irritation 

Rat 

2.34 ppm 

RD50

4 hours MRID 45117901 

Respiratory 

Irritation 400 ppb 

1,200 ppb 

rat & rabbit developmental: 

mortality, nasal staining 

6 hrs/day 

GD 7-29 (23 days) 

MRID 42740602/ 

42740601 

Respiratory 

Irritation 300 ppb 

1,000 ppb 

13-week rat & mouse: 

⁭ lung weights, histopath of 

nose and lungs 

6 hrs/day 

5 days/week 

13 weeks 

MRID 43063201 

Respiratory 

Irritation 100 ppb 

500 ppb 

chronic mouse: 

⁭ lung weights, histopath of 

nose, upper respiratory, and 

lungs 

6 hrs/day 

5 days/week 

108 weeks 

MRID 43632201 

3. Temporal Association: Regarding temporal association, it is apparent 

from the data in Table 2 that the timing or the onset of the key events is 

clearly identified in animals and humans. It is clear that chloropicrin at 

low concentrations (50 – 150 ppb) for up to one hour evokes trigeminal 

nerve sensations in the eyes without producing nasal or respiratory 

irritation. As concentration and duration of exposure increases 

sensations in the eyes evolves into eye irritation as well as sensations in 

the nose followed by nasal irritation. With continued chloropicrin 

exposure eye and nose irritation will develop into respiratory irritation. 

Respiratory irritation of the extrathoracic and pulmonary regions was 

evident in rodent studies with exposures of 6 to 8 hours per day for 30 

days to 2 years. The rodent studies, however, can not provide the timing 

Page 7 of 15 
of recognition of irritation. The human study evaluates concentrations 

and duration of exposure that are recognized by human subjects without 

producing adverse eye, nasal, or respiratory irritation. For example, a 

chamber concentration of 150 ppb for one hour produced eye recognition 

within 20-30 minutes without severe eye or nose irritation and no 

respiratory irritation. Respiratory irritation was quantified by a clinical 

exam of the eyes, nose, and throat, as well as pulmonary function testing 

including FEV1 (Forced Expiratory Volume) and FVC (Forced Vital 

Capacity), rhinomanometry, and nasal cytology. In addition, an 

assessment was performed based on ocular cytology from cell samples 

taken from the conjunctival membrane inside the lower eyelid and from 

the concentration of exhaled nitric oxide sampled from the lung (eNO) 

and nose (nNO). The rodent database does demonstrate, however, that 

increased chloropicrin concentrations can produce irritation within several 

minutes (1 hour) as in the RD50 mouse and acute rat inhalation study. 

Concentrations in the human study are orders of magnitude lower than 

concentrations evaluated in the rodent studies. 

4. Strength, consistency, and specificity of association of key events: The 

rodent database for chloropicrin demonstrates both the dose-response 

and temporal relationship of portal-of-entry effects. For example, 

congestion, bronchiole mucosal edema, necrosis and death were 

observed within 2 days following a 4 hour exposure to 10.6 ppm (10,600 

ppb) in the acute rat inhalation study. Histopathological lesions of the 

nasal cavity and lungs were observed after exposure for 6 hours/day, 5 

days/ week for 13 weeks at 1.0 ppm (1,000 ppb) in the subchronic 

inhalation studies while severe rhinitis of the anterior nasal cavity were 

observed at 0.5 ppm (500 ppb) in the chronic rat inhalation study. The 

robust database for chloropicrin supports the key events outlined in 

Figure 1. Furthermore both the concentration and duration of exposure 

are important in the onset of events and the time required between key 

events. As for the human study, chloropicrin clearly may evoke the 

sensation of feeling without producing irritation. Four consecutive days of 

1 hour exposures failed to produce eye or nose irritation such that 

recovery was immediate and with no day to day carryover effects. The 

feeling of chloropicrin in the eyes stopped or recovered with the cessation 

of the exposure. The point of departure (0.073 ppm) is based on the 

most sensitive subpopulation of the human population for sensory 

irritants. The point of departure is 2-fold lower than the concentration at 

which the most sensitive humans were capable of consistently detecting 

chloropicrin (0.15 ppm) in the eyes without severe eye, nose, throat, or 

respiratory irritation. All subjects had normal physiological parameters 

one hour after exposure. The point of departure (0.073 ppm) is 145-fold 

lower than the acute rodent inhalation study (10.6 ppm), 14-fold lower 

than irritation produced in repeat inhalation rodent studies (1.0 ppm) and 

14-fold lower than acute eye and respiratory effects observed in incident 

reports (1.0 ppm). 

5. Biological plausibility and coherence: This section of the MOA framework 

outlines whether the MOA is consistent with what is known about the 

endpoint. For chloropicrin, the temporal concordance and concentration 

Page 8 of 15 
dependence of eye irritation is consistent with the MOA and is biologically 

plausible. Coherence is addressed by evaluating both the animal and 

human data for the target tissue. Consistent port of entry effects are 

apparent in the rodent and human studies. Recognition of eye sensations 

is not possible in animals and therefore is addressed in the human study. 

Furthermore, chloropicrin behaves similarly to another sensory irritant 

such as carbon dioxide (CO2) (Stevens and Cain 1986; Kjaergaard et al 

1992; Shusterman et al 2001; Frasnelli and Hummel 2003; Shusterman et 

al 2003). As with chloropicrin, CO2 sensitivity decreases with age. 

6. Uncertainties, inconsistencies, and data gaps: Chloropicrin has a robust 

database, however, there are data gaps regarding the concentration and 

onset of key events beyond a 1 hour exposure in humans. This is due to 

the scientific and ethical considerations in evaluating humans in a 

laboratory setting. Concentrations producing severe irritation are not 

appropriate and therefore data for concentrations above 150 ppb are not 

available. Information regarding key events beyond 1 hour of exposure 

would be helpful in acute risk assessment. However, the current 

temporal concordance data suggest that as duration of exposure 

continues the sensation of eye feeling would not progress unless the 

concentration also increased. Current data suggest that as 

concentrations increase the onset and severity of irritation also increases 

or occurs earlier. Therefore, it would be expected that an exposure 

beyond one hour at currently evaluated concentrations (50-150 ppb) 

would not produce irritation. This is also supported by animal inhalation 

studies in which 6 hours of exposure per day for 13 weeks do not produce 

respiratory irritation up to 300 ppb. 

B. Intra-species Factor—Using chemical-specific information to refine the factor 

The IPSC Guidance document was published by WHO in 2005. This CSAF guidance 

describes approaches for use of kinetic and mechanistic data to refine inter-species and 

intra-species extrapolation factors. Understanding mode of action is an important 

component of deriving CSAFs/DDEFs in that MOA provides the foundation for 

understanding what toxicokinetic and/or toxicodynamic characteristics are critical for 

evaluating the intra-species factor. As described above, the chloropicrin MOA is well 

understood. 

When deriving data derived factors, the intra-species factor is separted into toxicokinetic 

and toxicodynamic components (UFHK and UFHD, respectively). Toxicokinetics (TK) is 

defined as the determination and quantification of the time course and dose dependency 

of absorption, distribution, metabolism, and excretion of chemicals (sometimes referred 

to as pharmacokinetics or ADME). Based on toxicokinetic characteristics, susceptibility 

is due to higher target tissue concentrations of the toxicant. Based on the mode of 

action of chloropicrin as a sensory irritant the target tissue is the eye, or stimulation of 

sensation in the eyes. Eye effects are more sensitive than nose (>12x) or lung (>100x). 

As demonstrated in the human study, sensation in the eyes is the most sensitive target. 

Air is the pathway of exposure where surface reaction with the trigeminal nerve evokes 

sensations in the eyes. Internal dose or target tissues are not a concern for chloropicrin 

since eyes are stimulated by surface concentrations. Therefore, based on the lack of 

Page 9 of 15 
ADME or the toxicokinetics for chloropicrin, the TK component of the intra-species factor 

(ie, UFHK) may be reduced to 1X. 

Toxicodynamics (TD) is defined as the determination and quantification of the sequence 

of events at the cellular and molecular levels leading to a toxic response. Three main 

questions are outlined in the IPCS guidance document for the determination of the 

adequacy of the experimental data for refinement of the toxicodynamic component. 

1. Relevance of population: The human subjects evaluated in the chloropicrin 

human study are considered to be the most sensitive subpopulation for sensory 

irritants. Participants in the human study were between the ages of 18 and 35 

(average 23 years). For age, sensory perception (both nasal and eye) is 

reported to decrease with increasing age (Kjaergaard et al., 1992; Frasnelli and 

Hummel, 2003; Hummel et al., 2003; Shusterman, 2003; Doty et al., 2004). The 

human subjects were exposed to the active parent compound via inhalation such 

that chloropicrin directly produced sensations in the target tissue (eyes). The 

severity of eye irritation was quantified as well as the response of the nasal and 

respiratory system. The eyes were clearly the most sensitive target with 

concentrations up to 150 ppb failing to produce lasting irritation in the eyes and 

no irritation in the nose, throat, or respiratory system. Therefore, the subjects 

evaluated in the chloropicrin human study are not only representative of all 

relevant age groups including both sexes, but the most sensitive subgroup. 

Furthermore, CO2, a sensory irritant, was tested in 158 subjects, including 1 

individual with asthma and 9 others with hayfever. CO2 proved no more sensitive 

in the upper airways and eyes during nonsymptomatic periods in these subjects 

nor did they differ from other subjects in their response to CO2 (Kjaergaard et al 

1992). Likewise, subjects with nasal allergies were similar to individuals of the 

same age to nasal detection to CO2 (Shusterman et al 2003). Finally, 

chloropicrin incident reports support consistent eye irritation across ages (3 

months to 63 years) for chloropicrin (1982-2002, D306838; 2002-2004, 

D305336). 

2. Adequacy of concentration-response data: All three phases of the human study 

provide timing of effects and the most sensitive target, namely the eyes. 

Specifically, Phase 3 of the human study provides adequate dose-response data 

for an acute assessment such that a BMCL10 which was performed on eye 

irritation data. The timing or onset of the eye irritation was also demonstrated 

such that 100 ppb took almost 60 minutes before recognition while 150 ppb 

produced sensations in the eyes within 20-30 minutes. The results of the human 

study correspond with the available literature regarding lower concentrations of 

chloropicrin. The data from both the human and animal data suggest that both 

concentration and duration of exposure are key components in the development 

of irritation, the onset of irritation, and the severity of the irritation. Concentrationresponse data for both human and animal data are outlined in Table 2. 

3. Adequacy of number of subjects/samples: The chloropicrin human study 

evaluated a total of 127 subjects with some subjects participating in more than 

one phase. This provides sufficient information for the most sensitive 

subpopulation for sensory irritants. The design of the study was based on the 

MOA and biochemical basis for this subgroup of individuals. The dose-response 

data from Phase 3 were utilized in the BMCL10 of 73 ppb. There was variability in 

Page 10 of 15 
the ability of these sensitive subjects to detect chloropicrin. This suggests that 

individuals less sensitive to the feeling of chloropicrin would not be capable of 

detecting at such low concentrations. At this low concentration, no irritation is 

produced since concentrations are not high enough to achieve surface reactions 

in the nose, throat, or respiratory system. The BMCL10 of 73 ppb is below a 

concentration detectable by the general population and therefore protective. 

Furthermore, there no susceptibility concerns since the developmental and 

reproductive rodent studies failed to identify any susceptible life stages. 

Incident data also provide key information to the toxicodynamics of chloropicrin. 

A report issued by the California Department of Pesticide Regulation (CDPR) 

and the Kern County Agriculture Commissionare (KACA) describes an 

investigation into illnesses associated with the offsite drift of chloropicrin in Kern 

County in 2003. Approximately 35 households and a day care center had a total 

of 172 persons present during the exposure period. A total of 165 persons 

experienced symptoms consistent with chloropicrin exposure. Age groups 

ranged from 3 months to 63 years of age. The number of individuals from each 

age group was similar with approximately 13% (22/165) 0-5 years, 10% (17/165) 

6-9 years, 14% (23/165) 10-14 years, 9% (15/165) 15-19 years, 11% (18/165) 

20-09 years, 13% (21/165) 30-39 years, 16% (26/165) 40-64 years, and 14% 

(23/165) age unknown. Nearly all individuals (99%; 163/165) reported symptoms 

of eye lacrimation or pain/burning, including children. Approximately 50% 

(85/165) of individuals experienced irritant symptoms of the upper respiratory 

system such as cough (53/165), dyspnea (27/165), upper respiratory irritation 

(22/165), chest pain (8/165) or asthma exacerbation (6/165). Exposure 

concentrations were retrospectively estimated by using a standard air dispersion 

model which indicated the peak-to-mean concentration may have exceeded 1 

ppm (1,000 ppb). This concentration was approximately 20-fold higher than 

concentrations evaluated in the chloropicrin human study (2005, MRID 

46443801). 

The symptoms reported in the 2003 Kern County chloropicrin incident are 

concordant with the sequence and onset of symptoms observed in the human 

study and animal database for chloropicrin. Specifically, the 2005 Cain human 

study demonstrates that even at low concentrations the eye is the most sensitive 

target for chloropicrin. Nearly all individuals in the Kern County incident, both 

young and old, reported eye irritation. Furthermore, the animal database 

demonstrates that as concentrations increase the potential for upper respiratory 

irritation increases. Individuals of the 2003 Kern County incident were exposed 

to concentrations greater than 20-fold higher (1 ppm or 1,000 ppb) than the Cain 

2005 human study (50-150 ppb or 0.05 – 0.15 ppm). As would be expected at 

these higher chloropicrin concentrations, upper respiratory irritation was reported 

in approximately 50% of individuals. Asthma exacerbation was only reported for 

approximately 6 of 165 persons (4%). This exacerbation was likely due to the 

high chloropicrin concentrations causing upper respiratory irritation. According to 

the American Lung Association (May 2006), Kern County reported approximately 

2.6% pediatric asthma (19,004 children /724,846 total population), 5.3% adult 

asthma (39,061 adults/ 724,846 total population), and 2.8% chronic bronchitis 

(20,617 individuals/ 724,846 total population). Therefore, the 4% of individuals 

reporting asthma exacerbation in Kern County is not above the County average, 

suggesting that chloropicrin did not induce asthma at a higher rate. Overall, the 

Page 11 of 15 
2003 Kern County reports symptoms consistent with those for chloropicrin, 

namely eye irritation being the most sensitive followed by upper respiratory 

irritation at higher concentrations. The similar number and type of symptoms 

among children and the older population suggest that individuals are capable of 

detecting chloropicrin and respond similarly to chloropicrin. 

Based on the known MOA for chloropicrin and the consistency and specificity of 

eye irritation in both young and old individuals from incident and literature 

studies, robust dose-response and temporal concordance of eye and irritation 

effects from the chloropicrin database, the TD component of the intra-species 

factor (ie, UFHD) may be reduced to 1X. Therefore, the overall intra-species 

factor for chloropicrin is reduced to 1X. 

III. MITC: Mode of Action and the Intra-Species Extrapolation Factor 

Recently, TERA, on behalf of AMVAC, submitted two reports: 

• Benchmark concentration modeling on the effects of acute exposure to 

Methyl Isothiocyanate (MITC). November 2007. 

• “Supplemental Report on the Effects of Acute Exposure To Methyl 

Isothiocyanate (MITC).” 

The benchmark concentration (BMC) report provides an analysis estimating benchmark 

concentration lower limit (BMCL) of 0.20 ppm based on a 4-hour human exposure from 

the human eye irritation study (Russell and Rush, 1996). The Agency appreciates the 

submission of this analysis and supports the use of benchmark approaches in risk 

assessment. The BMCL value provided by TERA of 0.20 ppm is similar to the point of 

departure of 0.22 ppm being used by EPA. As such, the BMCL analysis supports the 

Agency’s current approach. 

Following the submission of the BMC report, TERA and AMVAC met with EPA to 

discuss the BMC analysis and their proposal to reduce the intra-species factor to 1X. At 

that meeting, EPA staff requested additional information, particularly with regard to the 

mode of toxic action for MITC. In response to this request, TERA developed the second 

report noted above, herein called the “supplemental report.” 

The supplemental report describes a hypothesis for a mode of action by which MITC 

would affect the trigeminal nerve. Specifically, describes a hypothesis that MITC 

interacts with a group of cation channels known as the transient receptor potential (TRP) 

family (see also Bandell, Story, Hwang, et al., 2004). In particular the report suggests 

that TRPA1 may be the target. The Agency also acknowledges the work by TERA to 

characterize the human incidence information from California. This work is an important 

component of the weight of the evidence for MITC. 

Since the submission of the above reports, EPA has met with registrants and/or TERA 

on several occasions, most recently on June 18, 2008. At the June 18, 2008 meeting, 

Dr. William Cain provided the Agency with a publication by Jordt (2004). This 

publication includes data which shows MITC as a TRPA1 substrate. The Agency has 

not yet formally reviewed this study but it appears to provide by confirmation for the 

hypothesis described in the TERA reports. Based on further review, if this is indeed the 

case, then the Jordt study provides an important step forward in the hazard identification 

and characterization of MITC. Dose-response concordance is a critical element in the 

Page 12 of 15 
MOA Framework. Evaluation of dose response of key events and the relative sensitivity 

of different target organs provides the foundation for deriving points of departure for risk 

extrapolation and for deriving DDEFs, like that described for chloropicrin above. 

In the event that the MITC registrants decide to perform additional studies with MITC, 

the Agency suggests that the following key guidance/frameworks are consulted. These 

provide a roadmap for how the Agency will evaluate and ultimately use the mode of 

action information. 

• Mode of Action Framework as described in U.S. EPA (1999, 2005), SonichMullin et al. (2001), and Meek et al. (2003). This framework, based in large part 

on the Bradford-Hill criteria for determining causality in epidemiology studies, 

describes a framework for evaluating mode of action using animal and human 

data. This framework was used above for chloropicrin. In brief, this framework 

includes a statement regarding the postulated MOA and related key events 

followed with a discussion of dose-response and temporal considerations. 

Specifically, an understanding of the dose-response and relationships of eye 

and respiratory effects is a key area of consideration for MITC. An important 

component of any MOA analysis is the summary of strength, consistency, and 

specificity of key events, toxic effects, and biological plausibility and coherence. 

The analysis also considers the likelihood of alternative MOAs. In the case of 

MITC, relevance the postulated MOA for eye effects to other targets, such as the 

lung, should be considered. 

• IPSC Guidance on Chemical Specific Adjustment Factors (CSAFs, 2005). This 

guidance describes approaches for use of kinetic and mechanistic data to refine 

inter-species and intra-species extrapolation factors. The CSAF guidance is 

based on the principles 1) that TK and TD features of a compound both 

influence toxicity and 2) these TK and TD features can then be used to better 

inform inter- and intra-species extrapolation compared with the use of default 

factors. As stated above, understanding mode of action is an important 

component of deriving CSAFs in that mode of action provides the foundation for 

understanding what TK and/or TD characteristics are critical for evaluating interor intra-species extrapolation. In deriving CSAFs, each MOA–endpoint 

combination is individually evaluated. Thus, for MITC, based on the results of 

the dose-response evaluation in the MOA analysis (described above), EPA may 

develop CSAFs for any relevant effects (e.g., eye and respiratory). 

Conclusions 

The Agency considers all relevant information when performing risk assessments, 

especially with the fumigant compounds. For chloropicrin, the available data is outlined 

in the MOA framework and IPCS guidance on CSAFs in consideration of refinement of 

the intraspecies factor for eye irritation. For MITC, the body of information is growing on 

mode of action and human incidence. However, at this time, the dose response data 

needed for a concordance analysis and for DDEF derivation are not available. The 

Agency encourages the registrants to pursue this information. This information, in 

combination with qualitative MOA information and the human information, may provide 

opportunities to, consider refinements to the extrapolation and uncertainty factors which 

apply to MITC and ultimately to the margins of exposure used to estimate buffer zones. 

. 

Page 13 of 15 
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