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2003 (Memo, G. Kramer, et al., 10-MAR-2003; D275052). HED has evaluated the status of the 

human-health assessments for chlorfenapyr to determine whether sufficient data are available 

and whether any updates are needed to support Registration Review. HED considered the most 

recent human-health risk assessments for chlorfenapyr with respect to its toxicity, exposure, and 

usage databases, and the most updated Agency science policy and risk assessment methodologies 

to determine the scope of work necessary to support Registration Review. 

Chlorfenapyr has moderate acute toxicity via the oral route (Toxicity Category II) and low acute 

toxicity (Toxicity Category III) via the dermal and inhalation routes of exposure. It is a mild eye 

irritant but it is not a dermal irritant or sensitizer. The central nervous system (CNS) is the 

primary target of chlorfenapyr in rats and mice. Since the last risk assessment, a developmental 

neurotoxicity (DNT) study was submitted. There was no maternal toxicity seen up to the highest 

dose tested, while toxicity was seen in the pups at the mid-dose based upon pup deaths on 

postnatal day (PND) 1-4, and cannibalization and decreased motor activity in males and females 

on PND 13. The toxicology database for chlorfenapyr is essentially complete with the exception 

of an immunotoxicity study which is now required as a part of 40 CFR part 158. A 28-day 

dermal study in the rat and a 90-day inhalation study in the rat were requested by the Hazard 

Identification Assessment Review Committee (HIARC). 

The qualitative nature of chlorfenapyr residues in plants and livestock is adequately understood. 

The permanent tolerance expression for all commodities is in terms of parent only; however, 

chlorfenapyr dietary risk assessments should include, in addition to the parent, two chlorfenapyr 

metabolites for ruminant meat byproducts and four chlorfenapyr metabolites for poultry meat 

byproducts. The tolerance expression for chlorfenapyr needs to be updated to reflect current 

Agency policy: “Tolerances are established for residues of chlorfenapyr, including its 

metabolites and degradates, in or on the commodities in the table below. Compliance with the 

tolerance levels specified below is to be determined by measuring only chlorfenapyr, 4-bromo-2-

(4-chlorophenyl)-1-(ethoxymethyl)-5-(trifluoromethyl)-1H-pyrrole-3-carbonitrile, in or on the 

commodity.” 

The residue chemistry database is sufficient to support the current registrations. Livestock 

dietary burdens should be reassessed to evaluate potential secondary residues of chlorfenapyr 

and its metabolites in/on livestock commodities due to consumption of feed items with 

chlorfenapyr residues resulting from the established food/feed handling area use. Reference 

standards for three chlorfenapyr metabolites are currently expired or out of stock. Since parent 

only is the residue of concern, HED will not be requesting submission of new reference 

standards for these metabolites. 

The most recent acute and chronic dietary exposure assessments were below HED’s level of 

concern for the general U.S. population and all population subgroups examined. As part of 

registration review, however, a new dietary risk assessment is required which utilizes the most 

current version of the Dietary Exposure Evaluation Model software with the Food Commodity 

Intake Database (DEEM-FCIDTM; version 2.03), does not include DEEMTM default processing 

factors (which are not appropriate for an food handling establishment (FHE) use as residues 

would be expected to be incurred after processing) or citrus processing factors, and includes 

tolerances for the currently registered uses on greenhouse grown fruiting vegetable crop group 8 

commodities and FHE only. The new dietary exposure assessment should also evaluate potential 

secondary residues of chlorfenapyr and its metabolites in/on livestock commodities due to 

consumption of feed items with chlorfenapyr residues resulting from the established food/feed 
Chlorfenapyr Registration Review Human-Health Assessment Scoping Document 

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handling area use. Estimated drinking water concentrations (EDWCs) do not need to be 

incorporated into the dietary assessments as long as the existing or proposed uses of chlorfenapyr 

continue to not result in the contamination of drinking water. 

There is sufficient information available to assess residential exposure. Chlorfenapyr is 

registered as an insecticide/termiticide for residential pest control and can be applied as a crack 

and crevice/spot spray to indoor surfaces, as well as to the seams, folds and edges of mattresses. 

Application is restricted to pest management professionals; therefore, the only potential 

residential exposure is through post-application exposure (i.e., no residential handler exposure). 

Based upon the use pattern, post-application dermal, inhalation and incidental oral exposure is 

possible. A previous residential exposure assessment only included an assessment of 

postapplication inhalation exposure and therefore, a revised residential assessment is necessary 

to include the other routes of exposure. 

The 2003 risk assessment determined that because none of the use patterns for chlorfenapyr 

would result in contamination of drinking water or residential exposures, an aggregate risk 

assessment was not necessary. An aggregate risk assessment will need to be conducted once a 

revised residential post application assessment is available. 

There is sufficient information available to assess occupational handler exposure and postapplication exposure. Two occupational handler scenarios will need to be assessed during 

Registration Review and in addition, several occupational handler scenarios may need to be 

reassessed if changes are made to the hazard assessment. The occupational post application 

exposure assessment will need to be reassessed based on current labeled application rates and 

updated transfer coefficients and may also need to be reassessed in accordance with any 

proposed changes to the hazard assessment. 

There are no Codex or Canadian maximum residue limits (MRLs) established for chlorfenapyr. 

The U.S. and Mexican tolerance definitions are harmonized for residues of chlorfenapyr in/on 

commodities in fruiting vegetable crop group 8. There is an MRL of 0.5 ppm for cotton seed in 

Mexico which has no U.S. equivalent tolerance. Mexico adopts U.S. tolerances and/or Codex 

MRLs for export purposes. 

Introduction 

HED has evaluated the status of the human health assessments for chlorfenapyr to determine 

whether sufficient data are available and whether any updates are needed to support Registration 

Review. HED has considered the most recent risk assessment for chlorfenapyr (Memo, G. 

Kramer, et al., 10-MAR-2003; D275052); updates to its toxicity, exposure, and usage databases 

that have occurred since the last registration; and the most recently updated Agency science 

policy and risk assessment methodologies to determine the scope of work necessary to support 

Registration Review. In addition, HED conducted an open search to look for new literature 

relevant to the human-health risk assessment of chlorfenapyr. 

Chlorfenapyr is an insecticide/miticide currently registered for uses on greenhouse food and nonfood crops, and as an insecticide/termiticide for use on indoor and outdoor residential sites, 

food/feed handling areas, indoor and outdoor commercial sites (including sewers), and indoor 

medical sites. There are no residential handler uses for chlorfenapyr; the use on indoor and 

outdoor residential sites is for commercial applicators only. There is sufficient information 
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available to assess residential postapplication exposure and occupational handler exposure and 

post- application exposure. 

The qualitative nature of the residue in plants and livestock is considered to be adequately 

understood. The terminal residue of concern for plants, meat, milk, and poultry is chlorfenapyr 

only. The permanent tolerance expression for all commodities is in terms of parent only; 

however, chlorfenapyr dietary risk assessments should include, in addition to the parent, two 

chlorfenapyr metabolites for ruminant meat byproducts and four chlorfenapyr metabolites for 

poultry meat byproducts. The residue chemistry, toxicology, and occupational and residential 

exposure databases are sufficient to support the current registrations; however, there are some 

outstanding studies which, if submitted, would change the registration status from conditional to 

unconditional. 

Data requirements and risk assessment updates required under registration review for 

chlorfenapyr are as follows: 

• The following studies are required as specified in the new 40 CFR Part 158: 

o Guideline 870.7800, Immunotoxicity 

• The following studies as requested by the HIARC in 2003: 

o Guideline 870.3200, 21/28-Day Dermal 

o Guideline 870.3465, 90-Day Inhalation- rat 

• Livestock dietary burdens should be reassessed to evaluate potential secondary residues of 

chlorfenapyr and its metabolites in/on livestock commodities due to consumption of feed 

items with chlorfenapyr residues resulting from the established food/feed handling area 

use. 

• The tolerance expression for chlorfenapyr needs to be updated to reflect current Agency 

policy: “Tolerances are established for residues of chlorfenapyr, including its metabolites 

and degradates, in or on the commodities in the table below. Compliance with the 

tolerance levels specified below is to be determined by measuring only chlorfenapyr, 4-

bromo-2-(4-chlorophenyl)-1-(ethoxymethyl)-5-(trifluoromethyl)-1H-pyrrole-3-

carbonitrile, in or on the commodity.” 

• As part of registration review a new dietary risk assessment is required which utilizes the 

most current version of DEEM-FCIDTM (2.03), does not include DEEMTM default 

processing factors (which are not appropriate for an FHE use as residues would be 

expected to be incurred after processing) or citrus processing factors, and includes 

tolerances for the currently registered uses on greenhouse grown fruiting vegetable crop 

group 8 commodities and FHE only. The new dietary exposure assessment should also 

evaluate potential secondary residues of chlorfenapyr and its metabolites in/on livestock 

commodities due to consumption of feed items with chlorfenapyr residues resulting from 

the established food/feed handling area use. 

• As part of registration review, a revised residential postapplication and occupational 

handler and postapplication assessment will be necessary. The revised residential 

assessment will need to include dermal and incidental oral routes of exposure. Two 
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occupational handler scenarios will need to be assessed during Registration Review and 

in addition, several occupational handler scenarios may need to be reassessed if changes 

are made to the hazard assessment. The occupational post application exposure 

assessment will need to reassessed based on current labeled application rates and updated 

transfer coefficients and as well as any proposed changes to the hazard assessment. 

Hazard Identification/Toxicology

Chlorfenapyr is an insecticide/miticide and a member of the class of chemicals known as 

pyrroles. The toxicology database for chlorfenapyr is basically complete, with the exception of 

an acceptable 28-day dermal-toxicity study in the rat, a 90-day inhalation-toxicity study in the 

rat, and an immunotoxicity study in the rat. Chlorfenapyr has moderate acute toxicity via the 

oral route (Toxicity Category II) and low acute toxicity (Toxicity Category III) via the dermal 

and inhalation routes of exposure. It is a mild eye irritant but it is not a dermal irritant or 

sensitizer. Previously, the HIARC requested a subchronic neurotoxicity study. After a review of 

the chlorfenapyr hazard database, RAB1 toxicologists observed that a chronic neurotoxicity 

study had been performed. Because this study represents a “worst case” scenario, a subchronic 

neurotoxicity study is no longer required. 

The CNS is the primary target of chlorfenapyr in rats and mice. Subchronic and chronic dietary 

administration of chlorfenapyr to rats (males only) and mice (both sexes) induced 

neurohistological changes (vacuolar myelinopathy) in the white matter of the brain, spinal cord, 

and/or spinal nerve roots. The 80-week carcinogenicity study in mice exhibited a dose- and 

compound-related effect on the CNS (brain vacuolization), as well as vacuolization of the spinal 

cord and optic nerve at the high dose. In the subchronic mouse study, spongiform 

encephalopathy was noted in the white matter of the brain and myelin of the spinal cord in both 

sexes at the high dose. The chronic neurotoxicity study in rats revealed myelinopathic 

alterations in the CNS (brain, spinal cord, and spinal nerve roots) in male rats only. Myelin 

sheath swelling of spinal nerve roots was noted with dose-related incidences in treated males 

after both 13 and 52 weeks. The vacuolar myelinopathy was not associated with myelin or axon 

degeneration and was reversible following 16 weeks recovery. In the subchronic rat feeding 

study, spongiform myelinopathy (moderate) was noted in the brain and spinal cord of male rats. 

Although these cellular changes did not demonstrate a clear dose-response and did not affect 

clinical signs such as ataxia or locomotor activity, they are considered treatment-related because 

the findings are consistent with those seen in the chronic neurotoxicity rat study (males only), 

and the subchronic and carcinogenicity mouse studies (both sexes). In an acute neurotoxicity 

study, the rats in the high-dose group exhibited some neurobehavioral changes at functionalobservational-battery (FOB) testing on the day of dosing. The findings seen in both sexes 

included changes in gait, locomotion, arousal and lethargy (top two doses) on the day of 

treatment. The DNT study demonstrated no maternal toxicity up the highest dose tested, while 

toxicity was seen in the pups at the mid dose based upon pup deaths on PND 1-4, and 

cannibalization and decreased motor activity in males and females on PND 13. 

Subchronic and chronic toxicity studies in the dog showed generalized effects on body 

weight/body-weight gain. Emaciation and decreased food efficiency were also seen in the 

subchronic dog study. Body-weight decrements were also noted in the rat and/or mouse 

subchronic, chronic, and carcinogenicity studies, as well as in the developmental and 
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reproduction studies. Changes in hematology parameters consistent with anemia were also noted 

in the subchronic and chronic toxicity/carcinogenicity rat studies. 

The 2003 HIARC clarified, but did not change, the ambiguous 1996 cancer classification of 

“cannot be determined, suggestive” for chlorfenapyr. The HIARC indicated that, according to 

EPA’s July 1999 Draft Guidelines for Carcinogen Risk Assessment, the current classification 

category of “Suggestive Evidence of Carcinogenicity, but Not Sufficient to Assess Human 

Carcinogenic Potential” was a better description of the intent of the 1996 Cancer Peer Review 

Committee. 

There is no evidence (qualitative or quantitative) for increased susceptibility following in utero

exposure in the developmental toxicity studies in rats and rabbits or pre-/post-natal exposure in 

the two-generation reproduction study in rats. In both the rat and rabbit developmental toxicity 

studies, the mothers experienced decreased body-weight gain. No developmental toxicity was 

noted in rats up to the highest dose tested (225 mg/kg/day). Developmental toxicity in rabbits 

(increased post implantation loss) occurred at a higher dose than maternal toxicity. In the 2-

generation reproduction study in rats, parental and offspring toxicity included body-weight 

decrements at similar doses. No reproductive effects were noted up to the highest dose tested.

In a rat metabolism study, fecal excretion was the major route of elimination (80% of recovered 

radioactivity), with low recoveries of the radioactive chlorfenapyr in urine and tissues, indicating 

limited absorption. Most of the radioactivity was eliminated within 48 hours of dosing. Female 

rats had greater (about twice) recovery of radioactivity in the carcass, blood, and fat at all doses 

than did males. Parent compound was the major radioactive component found in excreta, 

accounting for approximately 40-70% of the administered doses. Minor amounts of eight 

primary and conjugated metabolites and four unidentified isolated components were detected, 

each at less than 10% of the dosed radioactivity. Liver and kidney contained several primary and 

conjugated metabolites and only minor levels of the parent compound (≤8.3% of the 

radioactivity in the sample). Based on the metabolites identified, the major deposition route of 

orally administered chlorfenapyr is fecal excretion of unaltered parent compound. Other 

pathways include cleavage of the ethoxymethyl side-chain, followed by de-alkylation and ring 

hydroxylation, and some degree of conjugation of the de-alkylated, ring-hydroxylated 

metabolite. The two rings of the molecule are not cleaved. Metabolites are excreted primarily in 

urine; accumulation in tissues is minimal. 

The endpoints used for risk assessment purposes from the most recent human-health risk 

assessment (Memo, G. Kramer, et al., 10-March-2003; D275052) can be found in Attachment 2. 

The FQPA section from the 2003 risk assessment was based upon policy developed in 2002. In 

2008, the FQPA policy was revised and updated (see Hot Sheet #30). Under the current policy, 

previous uncertainty factors which were utilized independently are now components of the 

FQPA safety factor. Since the last risk assessment, an acceptable DNT study was submitted and 

reviewed, and this study satisfies the data requirement for which a 10X UFDB (now called FQPA 

SF) was applied in the past. Despite the change in policy and submission of the required DNT 

study, the endpoint selection table attached in the Appendix has not been updated to reflect these 

changes. In future risk assessments for chlorfenapyr, the FQPA factor will need to be updated 

based upon the changes in policy, the submitted DNT study, as well as the submission of any 

studies which are currently missing. 
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Endocrine Disruption 

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor Screening 

Program (EDSP) to determine whether certain substances (including pesticide active and other 

ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally 

occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP 

employs a two-tiered approach to making the statutorily required determinations. Tier 1 consists of 

a battery of 11 screening assays to identify the potential of a chemical substance to interact with the 

estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 

screening and are found to have the potential to interact with E, A, or T hormonal systems will 

proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests 

are necessary based on the available data. Tier 2 testing is designed to identify any adverse 

endocrine related effects caused by the substance, and establish a dose-response relationship 

between the dose and the E, A, or T effect. 

Between October 2009 and February 2010, EPA is issuing test orders/data call-ins for the first group 

of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. This list of 

chemicals was selected based on the potential for human exposure through pathways such as food 

and water, residential activity, and certain post-application agricultural scenarios. This list should 

not be construed as a list of known or likely endocrine disruptors. 

Chlorfenapyr is not among the group of 58 pesticide active ingredients on the initial list to be 

screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide 

chemicals. Accordingly, EPA anticipates issuing future EDSP test orders/data call-ins for all 

pesticide active ingredients. 

Immunotoxicity 

An immunotoxicity study is required as a part of new data requirements in the 40 CFR Part 158 

for conventional pesticide registration. Because the immune system is highly complex, studies 

not specifically conducted to assess immunotoxic endpoints are inadequate to characterize a 

pesticide’s potential immunotoxicity. While data from hematology, lymphoid organ weights, 

and histopathology in routine chronic or subchronic toxicity studies may offer useful information 

on potential immunotoxic effects, these endpoints alone are insufficient to predict 

immunotoxicity. In the absence of required studies, EPA may use a database uncertainty factor 

of up to 10X. An immunotoxicity study on chlorfenapyr should be conducted (See Attachment 

6). Once all data have been received and reviewed, the chlorfenapyr Registration Review Team 

recommends that the points of departure and safety factors used for risk assessment purposes be 

reexamined and a new risk assessment done, if necessary. 

Conclusions 

The toxicity database is adequate to support existing registrations and registration review; 

however, as specified in the new 40 CFR Part 158 data requirements, an immunotoxicity study is 

required. In addition, the FQPA safety factor may need to be re-evaluated for future actions. 

Since the last risk assessment, a DNT study was submitted. The DNT study, along with the 

immunotoxicity, 28-dermal and 90-day inhalation studies when submitted, may lead to revision 

of the current endpoints for future risk assessments. 
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Residue Chemistry

Chlorfenapyr, 4-bromo-2-(4-chlorophenyl)-1-(ethoxymethyl)-5-(trifluoromethyl)-1H-pyrrole-3-

carbonitrile, is an insecticide/miticide used indoors, outdoors, and in greenhouses. Uses on 

fruiting vegetable crop group 8 (limited to those grown in greenhouses) and crack, crevice, and 

spot treatments of food/feed handling areas where food/feed products are prepared, held, 

processed, or served are the only food uses currently registered. There are no tolerances 

established for secondary residues in/on livestock commodities as a result of chlorfenapyr 

residues in livestock feed items. 

HED has previously received petitions for tolerances of chlorfenapyr residues in/on cotton, citrus 

(domestic and imported), head and leaf lettuce, broccoli, cauliflower, cabbage, potatoes, sweet 

potatoes, and field-grown tomatoes, eggplant, ground cherry, pepinos, and peppers, and livestock 

commodities based on these crop petitions; however, there are no established tolerances for these 

commodities aside from the tolerances established due to the fruiting vegetable crop group 8 

(limited to those grown in greenhouses) and FHE uses. HED also received a petition (Memo, G. 

Kramer, 19-AUG-1999; D247483) for the establishment of tolerances for residues of 

chlorfenapyr in/on meat and milk as a result of a cattle ear tag use; however, there currently are 

no established uses of chlorfenapyr in cattle ear tags. 

The nature of the residue in plants and livestock is adequately understood based on acceptable 

metabolism studies conducted on cotton, citrus, lettuce, potato, tomato, ruminants, and poultry 

(Memo, G. Otakie, 18-FEB-1994, D192275; Memo, G. Kramer, 08-AUG-1995, D215017; 

Memo, G. Otakie, 21-MAR-1996, D215977; Memo, G. Kramer, 01-FEB-1996, D218766; 

Memo, G. Otakie, 10-JUL-1996, D227383). Metabolism of chlorfenapyr in plants proceeds via: 

1) N-dealkylation of the parent compound; and 2) oxidation of the dealkylated metabolite. The 

permanent tolerance expression for all commodities is in terms of parent only; however, 

chlorfenapyr dietary risk assessments should include, in addition to the parent, two chlorfenapyr 

metabolites (CL 303,268 and 325,195) for ruminant meat byproducts and four chlorfenapyr 

metabolites (CL 303,268; 325,195; 152,835; and 325,157) for poultry meat byproducts (Memo, 

G. Otakie, 10-JUL-1996, D227383). The tolerance expression for chlorfenapyr needs to be 

updated to reflect current Agency policy: “Tolerances are established for residues of 

chlorfenapyr, including its metabolites and degradates, in or on the commodities in the table 

below. Compliance with the tolerance levels specified below is to be determined by measuring 

only chlorfenapyr, 4-bromo-2-(4-chlorophenyl)-1-(ethoxymethyl)-5-(trifluoromethyl)-1Hpyrrole-3-carbonitrile, in or on the commodity.” 

Acceptable tomato and orange processing studies have been submitted and reviewed (Memo, G. 

Kramer, 01-FEB-1996; D218766; Memo, G. Kramer, 06-AUG-1996; D222004). The tomato 

processing study indicated that residues did not concentrate in juice (reduction factor of 0.3X) 

and purée (reduction factor of 0.9X) and concentrated marginally in paste (1.8X). However, as 

greenhouse-grown tomatoes are not utilized for processing (personal communication with B. 

Schneider cited in Memo, G. Kramer, 28-SEP-2001; D276117), these data are not relevant to the 

uses of chlorfenapyr on greenhouse grown tomatoes and therefore should not be incorporated 

into the dietary exposure assessment unless a field-grown tomato use is established. The orange 

processing study indicated that residues of chlorfenapyr concentrate in oil (70X) and dried pulp 

(2.4X) and are not expected to concentrate in any citrus juice (<0.01X). The citrus processing 

data do not apply to the FHE tolerance on citrus and therefore should not be used in the dietary 

assessment unless a separate tolerance is established for chlorfenapyr residues in/on citrus. 
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A new dietary exposure assessment will need to be conducted which evaluates potential 

secondary residues of chlorfenapyr and its metabolites in/on livestock commodities due to 

consumption of feed items with chlorfenapyr residues resulting from the established food/feed 

handling area use. As a result, livestock dietary burdens should be reassessed to evaluate 

potential secondary residues of chlorfenapyr and its metabolites in/on livestock commodities. 

The standards for chlorfenapyr and the metabolites 4,5-dibromo-2-(4-chlorophenyl)-1H-pyrrole3-carbonitrile and 4-bromo-2-(3-chlorophenyl)-5-trifluoromethylpyrrole-3-carbonitrile are 

current until 01-OCT-2016, 01-JAN-2015, and 01-OCT-2017, respectively. Reference standards 

for chlorfenapyr metabolites 2,3-dichloropropionitriole (24270) and 2-chloroacrylonitrile 

(42637) expired on 01-MAY-2009 and the chlorfenapyr metabolite bromovinyl desbromo 

pyrrole (Z) is currently out of stock (personal communication with T. Cole, 10-FEB-2010). 

Since parent only is the residue of concern, HED will not be requesting submission of new 

reference standards. 

Conclusions

The qualitative nature of chlorfenapyr residues in plants and livestock is adequately understood. 

The terminal residues of regulatory concern in plants, meat, milk, and poultry is chlorfenapyr 

only. The permanent tolerance expression for ruminant and poultry meat byproducts should be 

in terms of parent only; however, chlorfenapyr dietary risk assessments should include, in 

addition to the parent, two chlorfenapyr metabolites for ruminant meat byproducts (CL 325,195 

[2-pyrrolidine-3-carbonitrile, 2-(p-chlorophenyl)-5-hydroxy-4-oxo-5-(trifluoromethyl)-} and CL 

322,250 [pyrrole-2-carboxylic acid, 3-bromo-5-(p-chlorophenyl)-4-cyano-]) and four 

chlorfenapyr metabolites for poultry meat byproducts (CL 303,268 [pyrrole-3-carbonitrile, 4-

bromo-2-(p-chlorophenyl)-5-(trifluoromethyl)-], CL 325,195 [2-pyrrolidine-3-carbonitrile, 2-(pchlorophenyl)-5-hydroxy-4-oxo-5-(trifluoromethyl)-], CL 152,835 [acetic acid, {[2-(pchlorophenyl)-3-cyano-5-(trifluoromethyl)pyrrol-1-yl]methoxy}-] and CL 325,157 [acetic acid, 

{[3-bromo-5-(p-chlorophenyl)-4-cyano-2-(trifluoromethyl)pyrrol-1-yl]). The residue chemistry 

database is sufficient to support the current registrations. 

The residue chemistry database is sufficient to support the current registrations. Livestock 

dietary burdens should be reassessed to evaluate potential secondary residues of chlorfenapyr 

and its metabolites in/on livestock commodities due to consumption of feed items with 

chlorfenapyr residues resulting from the established food/feed handling area use. Reference 

standards for three chlorfenapyr metabolites are currently expired or out of stock. Since parent 

only is the residue of concern, HED will not be requesting submission of new reference 

standards for these metabolites. 

Dietary Exposure

Acute and chronic dietary exposure assessments for chlorfenapyr were conducted in September 

of 2004 for the proposed use of chlorfenapyr in FHEs and all established uses (Memo, M. 

Hashim, 20-SEP-2004; D301322). The dietary exposure assessments were conducted using the 

DEEM- FCIDTM, Version 2.0, which incorporates consumption data from U.S. Department of 

Agriculture’s (USDA’s) Continuing Surveys of Food Intakes by Individuals (CSFII), 1994-1996 

and 1998. 

The acute and chronic Tier 1 dietary exposure analyses represented the chlorfenapyr residues 

with the published permanent and temporary tolerance values (section 3 and 18, respectively) as 
Chlorfenapyr Registration Review Human-Health Assessment Scoping Document 

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listed in 40 CFR §180.513 at the time of the assessment. A residue of 0.01 ppm was entered for 

all commodities except for the commodities in fruiting vegetable group 8 (1.0 ppm) and citrus oil 

(35 ppm). An assumption of 100% crop treated (%CT) was made. DEEMTM default values for 

processing factors were used for dried beef only (1.92X), and chemical specific processing 

factors for citrus juice (0.02X) were used in the inputs of the dietary exposure estimates. 

The citrus juice processing factor was based on a previously submitted and reviewed processing 

study (Memo, G. Kramer, 6-AUG-1996; D222004) and was included and translated to all citrus 

juices due to a previously pending imported citrus tolerance which currently has not been 

established (PP#6E4683; Memo, G. Kramer, 20-AUG-1999; D223893). As reported in the citrus 

processing memo (G. Kramer, 6-AUG-1996; D222004), the processing factor for citrus is 

<0.01X; therefore 0.01X should have been used instead of 0.02X. Since there are no currently 

established tolerances for citrus aside from the tolerances due to the FHE use, citrus processing 

factors, along with processing factors for commodities for which there are no established uses 

except for the FHE use, should not be included in the dietary exposure assessment unless 

additional use patterns and respective tolerances are established. Also, since greenhouse-grown 

tomatoes are not utilized for processing, tomato processing factors should not be incorporated 

into the dietary exposure assessment unless a field-grown tomato use is established. 

The most recent risk assessment stated that there are no existing or proposed uses of 

chlorfenapyr which would result in contamination of drinking water (Memo, G. Kramer, et al., 

10-MAR-2003; D275052). Accordingly, no EDWCs were incorporated into the 2004 acute and 

chronic dietary exposure assessments. 

For acute and non-cancer chronic exposures, HED is concerned when estimated dietary risk 

exceeds 100% of the population-adjusted dose (PAD). The acute and chronic dietary (food only) 

exposures to chlorfenapyr were below HED’s level of concern for the general U.S. population 

and all population subgroups examined. The acute dietary exposure resulted in a risk estimate 

that was 21% of the acute population-adjusted dose (aPAD) for females 13-49 years old at the 

95th exposure percentile and 8% of the aPAD for the general U.S. population. The chronic 

dietary exposure resulted in a risk estimate that was 35% of the chronic population-adjusted dose 

(cPAD) for the general U.S. population and 80% of the cPAD for children 1-2 years old, the 

most highly exposed population subgroup. 

Conclusions 

The most recent acute and chronic dietary exposure assessments were below HED’s level of 

concern for the general U.S. population and all population subgroups examined. As part of 

registration review, however, a new dietary risk assessment is required which utilizes the most 

current version of DEEM-FCIDTM (2.03), does not include DEEMTM default processing factors or 

citrus processing factors, and includes tolerances for the currently registered uses on greenhouse 

grown fruiting vegetable crop group 8 commodities and FHE only. The new dietary exposure 

assessment should also evaluate potential secondary residues of chlorfenapyr and its metabolites 

in/on livestock commodities due to consumption of feed items with chlorfenapyr residues 

resulting from the established food/feed handling area use. EDWCs do not need to be 

incorporated into the dietary assessments as long as the existing or proposed uses of chlorfenapyr 

continue to not result in the contamination of drinking water. 
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Residential Exposure

Chlorfenapyr is registered for residential (indoor and outdoor) and medical (indoor) uses. The 

representative residential use patterns, application rates and formulations are provided in 

Attachment 3. 

Residential Handlers

There are currently no registered residential uses that permit residential handlers. There is a 

registered insecticide/termiticide use that allows for applications in residential sites, for example, 

surfaces beneath cabinets and sinks, windows, and mattress seams. However, in the October 

2001 occupational/residential exposure assessment (Memo, M. Dow, 16-OCT-2001; D238777), 

it was stated that the label for review only allowed for application by Pest-Management 

Professionals. 

Residential Post-Application

HED has determined that there is potential for post-application exposure to adults and 

children/toddlers from the residential termiticide and crack and crevice/mattress applications of 

chlorfenapyr. Based on a review of the registered labels, there is potential for dermal, incidental 

oral, (for young children) and inhalations exposure resulting from this use. In the October 2001 

occupational/residential exposure assessment (Memo, M. Dow, 16-OCT-2001; D238777), a 

residential post-application exposure assessment was conducted; however, only post-application 

inhalation exposure was assessed. Since the vapor pressure of chlorfenapyr is <1.0 x 10-7 mmHg 

at 25C°, HED did not expect significant post-application inhalation exposure. As a screeninglevel assessment, HED utilized the Ideal Gas Law to estimate exposure at saturation of the 

material in the air. Because highly conservative, worst case assumptions resulted in margins of 

exposure (MOEs) ≥ levels of concern (LOC = 100), exposures did not exceed HED’s level of 

concern and are considered to be negligible. 

Conclusions 

Residential handler exposure is not permitted by the registered labels and is not expected. There 

is sufficient information available to assess residential post-application exposure from treated 

dwellings. A revised residential post application assessment is necessary for the crack/crevice 

and mattress applications to account for possible dermal and incidental oral exposures. HED is 

currently revising Residential Standard Operating Procedures (SOPs), including those used to 

determine exposure associated with crack and crevice and mattress treatments. Reviewers 

should incorporate new guidance from the updated SOPs to refine exposure estimates. 

Aggregate Risk Assessment 

Because there were no existing or proposed uses of chlorfenapyr which would result in 

contamination of drinking water or probable residential exposures, an aggregate risk assessment 

was not conducted as part of the last human-health risk assessment (Memo, G. Kramer, et al., 

10-MAR-2003; D275052). An aggregate risk assessment will need to be conducted once a 

revised residential post application assessment is completed. 

Occupational Exposure

Chlorfenapyr is registered for use on greenhouse food and non-food crops, and as an 

insecticide/miticide for use on indoor and outdoor residential sites, food/feed handling areas, 

indoor and outdoor commercial sites (including sewers), and indoor medical sites. A summary 
Chlorfenapyr Registration Review Human-Health Assessment Scoping Document 

Page 12 of 31 

of occupational uses is listed in Attachment 4. 

Occupational Handlers

HED has determined that occupational handlers are likely to be exposed to chlorfenapyr residues 

from the registered uses. In most cases, no chemical-specific data were available with which to 

assess potential exposure to pesticide handlers. Therefore, occupational handler assessments 

were based primarily on surrogate unit exposures from the Pesticide Handler's Exposure 

Database (PHED) as presented in the PHED Surrogate Exposure Guide. The risk calculations 

were based on the maximum application rates and assuming maximum area treated per day or 

gallons handled. Handler's exposure and risk were calculated at two levels of mitigation: 

baseline (long pants, a long-sleeved shirt, no chemical-resistant gloves, and no respirator) and 

personal-protective equipment (PPE; baseline clothing with chemical-resistant gloves when 

necessary). The representative occupational handler scenarios that have been assessed (or are 

covered by already assessed uses; i.e., a higher rate has already been assessed for the same 

formulation) are listed in Attachment 4. 

The most recent exposure assessment for pesticide handlers for the registered greenhouse use 

(fruiting vegetables) was conducted in March of 2003 (Memo, M. Dow, 07-MAR-2003; 

D288704). Provided that commercial pesticide handlers used label prescribed PPE (i.e., long 

pants, long-sleeved shirt, shoes + socks, and protective gloves), all assessed MOEs were not of 

concern to HED (i.e., MOEs were ≥ LOC = 100) at the maximum label rate of 0.2 lb ai/A (or 13 

fl oz/100 gallons). 

A 1999 assessment was conducted for chlorfenapyr use on ornamental plantings in greenhouses 

(Memo, D. Vogel, 29-NOV-1999; D241749), at a maximum application rate of 0.64 lb ai/A. All 

occupational handlers MOEs were not of concern to HED; however, the current label for this use 

lists the maximum application rate as 0.32 lb ai/100 gallons. 

Exposures and risks to handlers applying chlorfenapyr at a rate of 0.0469 lb ai/gal as a soil 

termiticide and crack and crevice spray (Memo, M. Dow, 16-OCT-2001; D238777) were below 

HED’s level of concern (MOEs ≥ LOC= 100). 

Occupational handler assessments have not been assessed for the following scenarios: 

• mixer/loader/applicator scenarios for aerosol can applications for all use sites; and 

• mixer/loader/applicator scenarios for high pressure spray application on non-edible 

greenhouse ornamentals at the current maximum label rate of 0.32 lb ai/100 gal. 

Conclusions

There is sufficient information available to assess occupational handler exposure. In addition to 

those scenarios that have not been assessed previously, several occupational handler scenarios 

may need to be reassessed if changes are made to the hazard assessment. 

Occupational Post-Application

Occupational post-application exposure is expected from the foliar uses of chlorfenapyr in 

greenhouses. Occupational post-application exposure is not expected from the termiticide and 

crack and crevice use in residential sites, indoor medical, indoor outdoor commercial sites, or 

food/feed handling establishments. 
Chlorfenapyr Registration Review Human-Health Assessment Scoping Document 

Page 13 of 31 

In most cases, no chemical-specific data were available with which to estimate post-application 

exposure of agricultural workers to dislodgeable residues of chlorfenapyr. HED does not expect 

significant post-application inhalation exposure since the vapor pressure of chlorfenapyr is <1.0 

x 10-7 mmHg. Post-application dermal exposure has been estimated using an HED procedure 

that assumes 20% of the application rate is available as dislodgeable foliar residue on the day of 

treatment. The HED Science Advisory Council for Exposure (ExpoSAC) Policy 003.1 lists a 

number of possible post-application agricultural activities relative to some of the subject crops 

that result in potential pesticide exposure to occupational workers. In most previous 

occupational exposure assessments, post-application exposures were calculated for the crop with 

the highest (i.e., most conservative) transfer coefficients. 

The most recent occupational post-application exposure assessment of chlorfenapyr was 

conducted in March of 2003 for activities associated with fruiting vegetables (Memo, M. Dow, 

07-MAR-2003; D288704). In that assessment, the following post-application activities for 

fruiting vegetables were assessed: hand harvest, pruning, staking, thinning, training, tying, 

scouting, and weeding. MOEs were not of concern to HED (i.e., MOEs were ≥ LOC = 100). 

Assessment of post-application inhalation exposure was deemed unnecessary due to the low 

vapor pressure of chlorfenapyr. Post-application exposure from greenhouse uses on non-edible 

ornamentals was assessed in November of 1999 (Memo, D. Vogel, 29-NOV-1999; D241749). 

In that assessment, irrigation activities were assessed as a high-end scenario and potential 

exposure did not exceed HED’s level of concern (MOEs were ≥ LOC = 100). However, postapplication exposure will need to be reassessed at the current maximum label rate of 0.32 lb 

ai/100 gal. Per changes to ExpoSAC Policy 003.1, the transfer coefficient for ornamentals will 

also need to be updated. 

Conclusions

There is sufficient information available to assess occupational postapplication exposure. In 

addition to the aforementioned revisions, the occupational post application exposure assessment 

may need to be reassessed if there are changes to the hazard assessment. 

Public Health and Pesticide Epidemiology Data 

A summary report listing incidents for chlorfenapyr reported to the OPP Incident Data System 

(IDS) has been provided for the docket (Memo, S. Winfield, 25-FEB-10; D373174). The report 

represents incidents occurring in the U.S. from 2002 to the present. 

Human Incident Data: OPP IDS (2010) 

For this evaluation, both the OPP Incident Data System (IDS) and 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) database were 

consulted for pesticide incident data on the active ingredient chlorfenapyr. Additionally, the 

Agency is looking to include findings from the Agricultural Health Study (AHS), beginning with 

the problem formulation phase of registration review. The purpose of the database searches is to 

identify potential patterns on the extent and severity of the health effects attributed to 

chlorfenapyr exposure. 

The IDS includes reports of alleged human health incidents from various sources, including 

mandatory Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) Section 6 (a) (2) reports 
Chlorfenapyr Registration Review Human-Health Assessment Scoping Document 

Page 14 of 31 

from registrants, other federal and state health and environmental agencies and individual 

consumers. Since 1992, OPP compiles these reports in IDS. IDS contains reports from across 

the U.S. and most incidents have all relevant product information recorded. Reports submitted to 

the IDS represent anecdotal reports or allegations only, unless otherwise stated in the report. The 

NIOSH SENSOR database covers 12 states from 1998-2006, although reporting varies from 

state to state (the database includes a total of 10,659 cases). Pesticide-related incidents are 

collected from Department of Labor workers’ compensation claims when reported by physicians, 

reports from State Departments of Agriculture, from poison control centers and from State 

Departments of Health based on reports by physicians suspecting pesticide exposure. Although 

both occupational and non-occupational incidents are included in the database, SENSOR focuses 

on occupational pesticide incidents, and is of particular value in providing that information. A 

state SENSOR contact specialist does follow-up with workers and obtains medical records to 

verify symptoms, circumstances surrounding the exposure, severity, and outcome. Using 

standardized protocol and case definitions, derived from poison center reporting, SENSOR 

coordinators at State Departments of Health enter the incident interview description provided by 

the worker, medical report, physician and patient into the SENSOR data system, accessible to 

participating states and EPA. 

The AHS is a high quality, prospective epidemiology study evaluating the link between pesticide 

use and various health outcomes including cancer. The AHS includes private and commercial 

pesticide applicators and their spouses. If there are AHS findings relevant to a particular 

pesticide going through registration review, the Agency will ensure they are considered in the 

problem formulation/scoping phase of the process and, if appropriate, fully reviewed in the risk 

assessment phase of the process. The AHS includes information on use of 50 different pesticide 

active ingredients commonly used in agriculture. 

For IDS, HED identified two incidents occurring in the United States from 2002 to the present 

for the single chemical (chlorfenapyr) only. One incident involved a person who experienced 

occupational exposure to his eyes while at work. The patient immediately flushed his eyes and 

the itchiness went away within few hours. The other case involved a patient with a history of 

brain surgery who developed seizures after being at home for 20-30 minutes while the product 

(Phantom) was applied and later developed seizures. 

Six cases were reported in the NIOSH SENSOR database that involved the active ingredient 

chlorfenapyr (from 1998-2006). Chlorfenapyr exposure was determined to be definite, probable, 

or possible in one of these cases where a 52-year-old female experienced an asthma attack after a 

nearby office was sprayed with Phantom Termiticide. The only symptoms reported were 

respiratory effects. This case was ranked as low severity. 

Chlorfenapyr is not included in the AHS, and therefore was not considered in the human incident 

report. 

Conclusions 

Based on the low severity and low number of incident cases, there does not appear to be a 

concern at this time that would warrant further investigation. The Agency will continue to 

monitor the incident information and if a concern is triggered, additional analysis will be 

included in the risk assessment. 
Chlorfenapyr Registration Review Human-Health Assessment Scoping Document 

Page 15 of 31 

Tolerance Assessment and International Harmonization 

U.S. permanent tolerances (listed in 40 CFR §180.513) and MRLs are summarized in 

Attachment 5. There are no Codex or Canadian MRLs established for chlorfenapyr. The U.S. 

and Mexican tolerance definitions are harmonized for residues of chlorfenapyr in/on 

commodities in fruiting vegetable crop group 8. There is an MRL of 0.5 ppm for cotton seed in 

Mexico which has no U.S. equivalent tolerance. Mexico adopts U.S. tolerances and/or Codex 

MRLs for export purposes. 

Environmental Justice 

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

human-health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations,” 

(http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf). The OPP 

typically considers the highest potential exposures from the legal use of a pesticide when 

conducting human-health risk assessments, including, but not limited to, people who obtain 

drinking water from sources near agricultural areas, the variability of diets within the U.S., and 

people who may be exposed when harvesting crops. Should these highest exposures indicate 

potential risks of concern, OPP further refines the risk assessments to ensure that the risk 

estimates are based on the best available information. 

Human Studies 

Past chlorfenapyr risk assessments rely in part on data from studies in which adult human 

subjects were intentionally exposed to a pesticide to determine their dermal and inhalation 

exposure. Many such studies, involving exposure to many different pesticides, comprise generic 

pesticide exposure databases such as the Pesticide Handlers Exposure Database (PHED) and the 

Agricultural Reentry Task Force (ARTF) Database. EPA has reviewed all the studies in these 

multi-pesticide generic exposure databases, and on the basis of available evidence has found 

them to have been neither fundamentally unethical nor significantly deficient relative to 

standards of ethical research conduct prevailing when they were conducted. There is no 

regulatory barrier to continued reliance on these studies, and all applicable requirements of 

EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been 

satisfied. 

Data Requirements and Risk Assessment Updates Required Under Registration Review 

Toxicology

• An acceptable 28-day dermal-toxicity study in the rat (not rabbit): The 28-day dermaltoxicity study in the rabbit was re-classified by the 01/21/03 HIARC as 

Unacceptable/Guideline due to incomplete histopathological evaluation. Histopathology 

was not performed on the minimum number of tissues as set forth in the guidance 

(870.3200), including brain tissue. Although the study was previously considered 

Acceptable, based on a re-evaluation of the database, the HIARC determined that the 

very limited histopathological examination is considered a significant deficiency. The 

HIARC has requested a new 28-day dermal-toxicity study in the rat, not the rabbit, which 

should include a full histopathological examination, including the brain and spinal cord. 
Chlorfenapyr Registration Review Human-Health Assessment Scoping Document 

Page 16 of 31 

• A 90-day inhalation-toxicity study in the rat: A subchronic inhalation-toxicity study was 

requested to characterize the direct effects of chlorfenapyr on the pulmonary system and 

any systemic effects via the inhalation route. This study should also include brain 

histopathology. This study was also requested by the HIARC.

• An immunotoxicity study as specified in the new 40 CFR Part 158.

Residue Chemistry 

• Livestock dietary burdens should be reassessed to evaluate potential secondary residues of 

chlorfenapyr and its metabolites in/on livestock commodities due to consumption of feed 

items with chlorfenapyr residues resulting from the established food/feed handling area 

use. 

• The tolerance expression for chlorfenapyr needs to be updated to reflect current Agency 

policy: “Tolerances are established for residues of chlorfenapyr, including its metabolites 

and degradates, in or on the commodities in the table below. Compliance with the 

tolerance levels specified below is to be determined by measuring only chlorfenapyr, 4-

bromo-2-(4-chlorophenyl)-1-(ethoxymethyl)-5-(trifluoromethyl)-1H-pyrrole-3-

carbonitrile, in or on the commodity.” 

Dietary Exposure

• As part of registration review a new dietary risk assessment is required which utilizes the 

most current version of DEEM-FCIDTM (2.03), does not include DEEMTM default 

processing factors (which are not appropriate for an FHE use as residues would be 

expected to be incurred after processing) or citrus processing factors, and includes 

tolerances for the currently registered uses on greenhouse grown fruiting vegetable crop 

group 8 commodities and FHE only. The new dietary exposure assessment should also 

evaluate potential secondary residues of chlorfenapyr and its metabolites in/on livestock 

commodities due to consumption of feed items with chlorfenapyr residues resulting from 

the established food/feed handling area use. 

Occupational and Residential Exposure

• As part of registration review, a revised residential postapplication and occupational 

handler and postapplication assessment will be necessary. The revised residential 

assessment will need to include dermal and incidental oral routes of exposure. Two 

occupational handler scenarios will need to be assessed during Registration Review and in 

addition, several occupational handler scenarios may need to be reassessed in accordance 

with changes to the hazard assessment. The occupational post application exposure 

assessment will need to reassessed based on current labeled application rates and updated 

transfer coefficients and may also need to be reassessed in accordance with changes to the 

hazard assessment. 
Chlorfenapyr Registration Review Human-Health Assessment Scoping Document 

Page 17 of 31 

References 

Memoranda Relevant to Registration Review. 

Author DP Barcode Date Title 

S. Chun D257550 22-JUL1999 

Chlorfenapyr - Acute and Chronic Dietary Exposure Analyses. 

Chemical#: 129093. DP Barcode: D257550. Case #: 287432. 

Submission #: S563946. 

R. Cook D226458 

21-

NOV1996 

PP6F4716. Chlorfenapyr on Potatoes, Sweet Potatoes, Head Lettuce, 

Leaf Lettuce, Cabbage, Cauliflower, Tomatoes, Eggplants, Peppers, 

Pepinos, and Ground Cherries. Evaluation of Analytical Methods, 

Field Trial and Processing Residue Data. CBTS 17220. 

M. Dow 

D238777, 

D255715, 

D255758, 

D277150 

16-

OCT2001 

Exposure/Risk Assessment for Pesticide Handlers and Residents from 

Post-Construction Terimiticide or Crack and Crevice Use. 

M. Dow D266948 

26-

NOV2001 

Review of PhantomTM (Chlorfenapyr-CL 30630): Determination of 

Indoor Air Concentrations of Chlorfenapyr after Application of 

PHANTOMTM 2SC Termiticide-Insecticide Applied as a Termiticide 

Treatment to Basement and Crawl Space Construction Housing.

M. Dow D288704 

07-

MAR2003 

Exposure/Risk Assessment for Pesticide Handlers and Agricultural 

Workers from Greenhouse Use. 

M. Hashim D301322 20-SEP2004 

Chlorfenapyr: Acute and Chronic Dietary Exposure Analyses for 

Section 3 Use of Chlorfenapyr in food-handling establishments. 

J. Kidwell TXR0051606 

04-

MAR2003 

Chlorfenapyr- Second Report of the Hazard Identification Assessment 

Review Committee. 

G. Kramer D217271 18-JUL1995 

PP# 5G04507. Alert in or on Oranges and Lemons. Request for 

Petition Method Validation. MRID# 436221-02. Barcode D217271. 

Chemical No 129093. CBTS# 15867. 

G. Kramer D215017 

08-

AUG1995 

PP# 5G04507. Alert in or on Oranges and Lemons. Evaluation of 

residue data and analytical methods. Chemical No 129093. MRID#s 

436221-01 thru -04. Barcodes D215017 & D216197. CBTS#s 15682 & 

15841. 

G. Kramer D218766 

01-

FEB1996 

PP# 5G04574. Alert in or on Tomatoes. Evaluation of Residue Data 

and Analytical Methods. Chemical No 129093. MRID#s 437536-01 

thru -04. Barcode D218766. CBTS# 16070. 

G. Kramer D222327 

29-

FEB1996 

PP# 5G04507. AC 303630 (Alert) in or on Oranges and Lemons. 

Results of Petition Method Validation (PMV). MRID# 436221-02. 

Barcode D222327. Chemical No 129093. CBTS# 16746. 

G. Kramer D222004 6-AUG1996 

PP# 6F04623. Chlorfenapyr (i.e. Alert/Pirate®) in/on Citrus. Evaluation 

of Residue Data and Analytical Methods. MRID#s 438359-01 thru -03. 

Chemical 129093. Barcode D222004. CBTS# 16763. Case 287132. 

G. Kramer D226878 

29-

OCT1996 

PP# 6E04683. Chlorfenapyr (i.e. Alert/Pirate®) in/on Imported Citrus. 

Evaluation of Residue Data and Analytical Methods. MRID# 439363-

01. Chemical 129093. Barcode D226878. CBTS# 17260. Case 

287432. 

G. Kramer D221320 

12-

FEB1998 

Chlorfenapyr - 129093: Health Effects Division Risk Characterization 

for Use of the Chemical Chlorfenapyr (Alert, EPA File Symbol 5905-

GAI) in/on Citrus (6F04623). Case: 287132. Barcode: D221320. 

G. Kramer D247483 

19-

AUG1999 

PP# 8F04980. Chlorfenapyr (i.e. Chlorfenapyr Insecticide Cattle Ear 

Tag) in/on Meat & Milk. Evaluation of Residue Data and Analytical 

Methods. MRID# 445603-02. Chemical 129093. Barcodes D247483, 

D247491, & D247498. Cases 290113, 062365, & 044966. Submission 

#s S544727, S544730, & S545357. 

G. Kramer D223893 

20-

AUG1999 

PP# 6E04683. Chlorfenapyr (i.e. Alert/Pirate®) in/on Imported Citrus. 

Amendments of 6/21/99, 7/20/99, & 8/9/99. Revised Sections B & F. 

Barcodes D223893, D226878, D257074, D257884, & D258558. 
Chlorfenapyr Registration Review Human-Health Assessment Scoping Document 

Page 18 of 31 

Memoranda Relevant to Registration Review. 

Author DP Barcode Date Title 

Chemical 129093. Case 287432. Submissions S501617, S563946, 

S565559, & S566570. 

G. Kramer D259238 24-SEP1999 

PP# 8F04980. Chlorfenapyr (i.e. Chlorfenapyr Insecticide Cattle Ear 

Tag) in/on Meat & Milk. Amendment of 9/7/99. Revised Section F. 

MRID# none. Barcode D259238. Chemical 129093. Case 290113. 

Submission S567814. 

G. Kramer D265082 

05-

MAY2000 

PP# 6E04683. Chlorfenapyr (i.e. Alert/Pirate®) in/on Imported Citrus. 

Review of Amendment Dated 3/30/00 Submitted in Response to HED’s 

Memo of 8/20/99. Revised Section F and Enforcement Method and 

Additional Residue Data. MRID#s 450851-01 to -03. Barcode 

D265082. Chemical 129093. Case 287432. Submission S578413. 

G. Kramer D276117 28-SEP2001 

PP# 6F04716. Chlorfenapyr On Fruiting Vegetables Grown In 

Greenhouses. Evaluation of Residue Data and Analytical Methods. 

MRID#s 451198-02 thru -04. Chemical 129093. Barcode D276117. 

Case 287746. Submission S597379. 

G. Kramer D276749 

17-

JAN2002 

ID#: 000241 00392. Evaluation of Residue Chemistry Data to Support 

Nonfood Use Classification of Chlorfenapyr in Food-Handling 

Establishments. MRID# 448441 01. Chemical 129093. Barcode 

276749. Case 061931. Submission S601249. 

G. Kramer D275052 

10-

MAR2003 

PP# 7F4716. Chlorfenapyr On Fruiting Vegetables Grown In 

Greenhouses. Health Effects Division (HED) Risk Assessment. DP 

Barcode D275052. Chemical No. 129093. Case 287746. Submission 

S597379. 

G. Kramer D289382 

15-

MAY2003 

PP# 7F4716. Chlorfenapyr On Fruiting Vegetables Grown In 

Greenhouses. Review of Amendment Dated 5/5/03 Submitted in 

Response to HED’s Memo of 9/28/01. Revised of Analytical 

Enforcement Method for Plants and Sections B & F. MRID# 

45923401. Barcodes D289382 & D289863. Chemical 129093. Case 

287746. Submission#s S632737 & S634554. 

G. Otakie D192275 

18-

FEB1994 

PP#3G4224 - New Chemical - Pirate Insecticide on Cotton. Evaluation 

Of Product and Residue Chemistry Data. MRID Nos. 427702-01 thru 

06 and 427702-34 thru 39. CBTS Nos. 12023, 12292, and 12293. DP 

Barcodes D192275, D193607 and D193607. 

G. Otakie D215977 

21-

MAR1996 

PP#5G04523 and PP#5G04548 - New Chemical - Alert/Pirate (i.e. 

Cholrfenapyr [sic]) on Lettuce and Cabbage (also known as Pirate). 

Evaluation of Residue Data and Analytical Methods Field Trial and 

Processing Residue Data. MRID Nos. 436389-01 thru -04 and 437007-

01 thru -02. (CBTS Nos. 15661 and 15833). DP Barcodes: D215977 

and D217117. 

G. Otakie D227383 10-JUL1996 

HED Metabolism Committee Meeting of 6/20/96. New Chemical - 

Chlorfenapyr (i.e. Alert/Pirate®). PP#5F04456. Insecticide/Miticide on 

Cotton/Oranges/Lemons and Tomatoes/Lettuce/Cabbage/Potatoes. 

Barcode D227383. CBTS# 17304. 

J. Tyler D279174 

19-

FEB2003 

Chlorfenapyr. Acute and Chronic Dietary Exposure Assessments for 

Requests for Tolerances on Fruiting Vegetables Grown in Greenhouses. 

PP# 6F04716. PC Code 129093. DP Barcode D279174. Case 

287746. Submission S597379. 

D. Vogel D241749 

29-

NOV1999 

Occupational Exposure and Risk Assessment/Characterization for 

Chlorfenapyr use in Greenhouse and Shadehouses. 

Attachments 

Attachment 1: Chemical Identity Tables 
Chlorfenapyr Registration Review Human-Health Assessment Scoping Document 

Page 19 of 31 

Attachment 2: Chlorfenapyr Endpoint Selection Table 

Attachment 3: Residential Exposure Table 

Attachment 4: Occupational Use Patterns/ Exposure Scenarios for Chlorfenapyr 

Attachment 5: Chlorfenapyr International Residue Limit Status 

Attachment 6: DCI Justification for Dermal Studies 

Attachment 7: DCI Justification for Inhalation Studies 

Attachment 8: DCI Justification for Immunotoxicity Studies 
Chlorfenapyr Registration Review Human-Health Assessment Scoping Document 

Page 20 of 31 

Attachment 1: Chemical Identity Tables 

Chemical Identity of Chlorfenapyr. 

Common name Chlorfenapyr 

PC Code 129093 

IUPAC Name 4-bromo-2-(4-chlorophenyl)-1-ethoxymethyl-5-trifluoromethyl-1H-pyrrole-3-

carbonitrile 

CAS name 4-bromo-2-(4-chlorophenyl)-1-(ethoxymethyl)-5-(trifluoromethyl)-1H-pyrrole-3-

carbonitrile 

CAS registry number 122453-73-0 

Registration Review Case No. 7419 

Chemical Formula C15H11BrClF3N2O 

Chemical structure 

Physical and Chemical Properties for Chlorfenapyr. 

Parameter Value Reference 

Color light tan or light yellow 

Physical State powdered solid 

Odor characteristic of halides and ketones 

Melting Point melting point apparatus 100-101° C 

Boiling Point n/a; technical grade of the active ingredient (TGAI) is a 

solid 

Density, Bulk Density, or 

Specific Gravity 

0.543 g/mL tapped bulk density 0.355 g/mL untapped bulk 

density 

Solubility 

 Solvent Solubility at 25oC 

deionized water 0.12 mg/mL 

water, pH 4 0.13 mg/l 

water, pH 7 0.14 mg/l 

water, pH 10 0.12 mg/l 

hexane 0.89 g/100 mL 

methanol 7.09 g/100 mL 

acetonitrile 68.4 g/100 mL 

toluene 75.4 g/100 mL 

acetone 114 g/100 mL 

dichloromethane 141 g/100 mL 

Vapor Pressure <1.0 x 10-7 mm Hg at 25°C 

Dissociation Constant since there are no ionizable groups in the chlorfenapyr 

structure, no dissociation will occur (PAI) 

Octanol/Water Partition 

Coefficient Kow = 67,670 (log Kow = 4.83) at 25°C 

pH 7.16; 1% aqueous slurry at 24°C 

Memo, G. 

Kramer et al., 12-

FEB-1998; 

D221320 
Chlorfenapyr Registration Review Human-Health Assessment Scoping Document 

Page 21 of 31 

Attachment 2: Chlorfenapyr Endpoint Selection Table 

Summary of Toxicological Doses and Endpoints for Chlorfenapyr Used in 2003 Human-health Risk 

Assessments1. 

Exposure 

Scenario

Dose Used in Risk 

Assessment, UF

Level of Concern for 

Risk Assessment

Study and Toxicological 

Effects

Acute Dietary 

(Females 13-50 years of 

age)

NOAEL = 15 mg/kg 

UF = 1000 

aRfD = 0.015 mg/kg

aPAD = aRfD 

 FQPA SF 

= 0.015 mg/kg 

Developmental Toxicity 

Study - Rabbit 

LOAEL = 30 mg/kg/day 

based on increased postimplantation loss.

Acute Dietary 

(General population 

including infants and 

children)

NOAEL = 45 mg/kg 

UF = 1000 

aRfD = 0.045 mg/kg 

aPAD = aRfD

 FQPA SF 

= 0.045 mg/kg

Acute Neurotoxicity 

Study - Rat

LOAEL = 90 mg/kg/day 

based on lethargy in male 

rats.

Chronic Dietary 

(All populations)

NOAEL = 2.6 mg/kg/day 

UF = 1000 

cRfD = 0.003 

mg/kg/day 

cPAD = cRfD

 FQPA SF 

= 0.003 mg/kg/day

Chronic Neurotoxicity 

Study - Rat 

LOAEL = 13.6/18 

mg/kg/day, M/F, based on 

the presence of 

myelinopathic alterations 

in the CNS in male rats 

and decreased average 

body weights, bodyweight gains, food 

efficiency, absolute food 

consumption (F), and 

water consumption (M). 

Supporting this endpoint

are similar CNS lesions 

and skin lesions observed 

in the mouse 

carcinogenicity study 

(NOAEL = 2.8).

Short-Term Oral 

(1-30 days) 

Oral study NOAEL = 3.9 

mg/kg/day

Residential LOC for 

MOE = 1000 

Occupational = NA

90-Day Feeding Study - 

Dog 

LOAEL = 6.7/6.8 

mg/kg/day, M/F, based on 

emaciation, decreased 

body-weight gains, and 

decreased food efficiency.

Intermediate-Term Oral 

(1-6 months) 

Oral study NOAEL = 3.9 

mg/kg/day

Residential LOC for 

MOE = 1000 

Occupational = NA

90-Day Feeding Study - 

Dog 

LOAEL = 6.7/6.8 

mg/kg/day, M/F, based on 

emaciation, decreased 

body-weight gains, and 

decreased food efficiency.

Short-Term Dermal (1-30 

days)

Oral study NOAEL = 3.9 

mg/kg/day 

(dermal-absorption rate = 

5%)

Residential LOC for 

MOE = 1000 

 Occupational = 100

90-Day Feeding Study - 

Dog 

LOAEL = 6.7/6.8 

mg/kg/day, M/F, based on 

emaciation, decreased 

body-weight gains, and 

decreased food efficiency.
Chlorfenapyr Registration Review Human-Health Assessment Scoping Document 

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Summary of Toxicological Doses and Endpoints for Chlorfenapyr Used in 2003 Human-health Risk 

Assessments1. 

Exposure 

Scenario

Dose Used in Risk 

Assessment, UF

Level of Concern for 

Risk Assessment

Study and Toxicological 

Effects

Intermediate-Term 

Dermal (1-6 months)

Oral study NOAEL = 3.9 

mg/kg/day 

(dermal-absorption rate = 

5%)

Residential LOC for 

MOE = 1000 

Occupational = 100

90-Day Feeding Study - 

Dog 

LOAEL = 6.7/6.8 

mg/kg/day, M/F, based on 

emaciation, decreased 

body-weight gains, and 

decreased food efficiency.

Long-Term Dermal (>6 

months)

oral study NOAEL = 2.6 

mg/kg/day 

(dermal-absorption rate = 

5%)

Residential LOC for 

MOE = 1000 

Occupational = 100

Chronic Neurotoxicity 

Study - Rat 

LOAEL = 13.6/18 

mg/kg/day, M/F, based on 

the presence of 

myelinopathic alterations 

in the CNS in male rats 

and decreased average 

body weights, bodyweight gains, food 

efficiency, absolute food 

consumption (F), and 

water consumption (M). 

Supporting this endpoint

are similar CNS lesions 

and skin lesions observed 

in the mouse 

carcinogenicity study 

(NOAEL = 2.8).

Short-Term Inhalation (1 

to 30 days) 

Oral study NOAEL= 3.9 

mg/kg/day 

(inhalation absorption rate 

= 100%)

Residential LOC for 

MOE = 1000 

Occupational = 100

90-Day Feeding Study - 

Dog 

LOAEL = 6.7/6.8 

mg/kg/day, M/F, based on 

emaciation, decreased 

body-weight gains, and 

decreased food efficiency.

Intermediate-Term 

Inhalation (1 to 6 months) 

Oral study NOAEL= 3.9 

mg/kg/day 

(inhalation absorption rate 

= 100%)

Residential LOC for 

MOE =1000 

Occupational = 100

90-Day Feeding Study - 

Dog 

LOAEL = 6.7/6.8 

mg/kg/day, M/F, based on 

emaciation, decreased 

body-weight gains, and 

decreased food efficiency.

Long-Term Inhalation (>6 

months) 

inhalation (or oral) study 

NOAEL=2.6 mg/kg/day 

(inhalation absorption rate 

= 100%)

Residential LOC for 

MOE =1000 

Occupational = 100

Chronic Neurotoxicity 

Study - Rat 

LOAEL = 13.6/18 

mg/kg/day, M/F, based on 

the presence of 

myelinopathic alterations 

in the CNS in male rats 

and decreased average 

body weights, bodyweight gains, food 

efficiency, absolute food 

consumption (F), and 

water consumption (M). 
Chlorfenapyr Registration Review Human-Health Assessment Scoping Document 

Page 23 of 31 

Summary of Toxicological Doses and Endpoints for Chlorfenapyr Used in 2003 Human-health Risk 

Assessments1. 

Exposure 

Scenario

Dose Used in Risk 

Assessment, UF

Level of Concern for 

Risk Assessment

Study and Toxicological 

Effects

Supporting this endpoint

are similar CNS lesions 

and skin lesions observed 

in the mouse 

carcinogenicity study 

(NOAEL = 2.8).

Cancer (oral, dermal, 

inhalation)

Classified as “Suggestive Evidence of Carcinogenicity, 

but Not Sufficient to Assess Human Carcinogenic 

Potential.” 

A cancer risk assessment is not required.

Dietary/Dermal/Inhalation

1

 UF = uncertainty factor, FQPA SF = FQPA SF, NOAEL = no-observed adverse-effect level, LOAEL = lowestobserved adverse-effect level, PAD = population-adjusted dose (a = acute, c = chronic), RfD = reference dose, MOE 

= margin of exposure, LOC = level of concern.
Chlorfenapyr Registration Review Human-Health Assessment Scoping Document 

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Attachment 3: Residential Exposure Table 

Summary of Representative Residential Use Patterns, Formulations and Application Rates for Chlorfenapyr. 

Scenario Covered? Crop / Site Formulationa Equipment Max App Rate Qty M/L/A Postapp. 

Residential post-application only (PCO applied) 

Household/domestic PRL Aerosol can 0.5% ai Y N 

dwellings indoor premises EC Low pressure 0.0469 lb/gal Y N 

PRL Aerosol can 0.5% ai Y N 

0.0469 lb/gal Household/domestic 

dwellings outdoor premises EC Low pressure 2.17E-04 lb sq. ft Y N 

a. PRL = pressurized release liquid ; EC =emulsifiable concentrate. 

b. M/L/A = mixer/loader/applicator. 

Attachment 4: Occupational Use Patterns/ Exposure Scenarios for Chlorfenapyr 

Summary of Representative Occupational Use Patterns, Formulations, and Application Rates for Chlorfenapyr. 

Scenario covered? 

Crop / Site Formulationa Application 

Equipment 

Maximum 

application 

rates Mixer/ 

loader Applicator M/L/Ab 

PRL Aerosol 

can 

0.5% ai N/A N/A N 

Commercial storages/warehouse premises 

EC 

Lowpressure 

handwand 

0.0469 

lb/gal N/A N/A Y 

PRL Aerosol 

can 

0.5% ai N/A N/A N 

Commercial/institutional/industrial 

premises/equip. (indoor) EC 

Lowpressure 

handwand 

0.0469 

lb/gal N/A N/A Y 

PRL Aerosol 

can 

0.5% ai N/A N/A N 

Dairies/cheese processing plant equipment 

(food contact)c 

EC 

Lowpressure 

handwand 

0.0469 

lb/gal N/A N/A Y 

PRL Aerosol 

can 

0.5% ai N/A N/A N 

Eating establishments 

EC 

Lowpressure 

handwand 

0.0469 

lb/gal N/A N/A Y 

PRL Aerosol 

can 

0.5% ai N/A N/A N 

Egg packing plants (commercial)c 

EC 

Lowpressure 

handwand 

0.0469 

lb/gal N/A N/A Y 

Eggplant (greenhouse) SCb 

Highpressure 

handwand 

0.20 lb 

ai/A N/A N/A Y 
Chlorfenapyr Registration Review Human-Health Assessment Scoping Document 

Page 25 of 31 

Summary of Representative Occupational Use Patterns, Formulations, and Application Rates for Chlorfenapyr. 

Scenario covered? 

Crop / Site Formulationa Application 

Equipment 

Maximum 

application 

rates Mixer/ 

loader Applicator M/L/Ab 

PRL Aerosol 

can 

0.5% ai N/A N/A N 

Feed mills/ feed processing plants 

EC 

Lowpressure 

handwand 

0.0469 

lb/gal N/A N/A Y 

Food processing plant equipment (food 

contact) EC 

Lowpressure 

handwand 

0.0469 

lb/gal N/A N/A Y 

Food processing plant equipment (nonfood 

contact) PRL Aerosol can 

0.5% ai N/A N/A N 

Food stores/markets/supermarkets premises EC 

Lowpressure 

handwand 

0.0469 

lb/gal N/A N/A Y 

PRL Aerosol 

can 

0.5% ai N/A N/A N 

Food/grocery/marketing/storage/distribution 

facility premise EC 

Lowpressure 

handwand 

0.0469 

lb/gal N/A N/A Y 

Fruiting vegetables (greenhouse) SCb

High 

pressure 

handwand 

0.20 lb 

ai/A N/A N/A Y 

Groundcherry (strawberry tomato/tomatillo) 

(greenhouse) SCc 

Highpressure 

handwand 

0.20 lb 

ai/A N/A N/A Y 

PRL Aerosol 

can 

0.5% ai N/A N/A N 

Hospitals/medical institutions premises 

(human/veterinary) EC 

Lowpressure 

handwand 

0.0469 

lb/gal N/A N/A Y 

PRL Aerosol 

can 

0.5% ai N/A N/A N 

EC 

Lowpressure 

handwand 

0.0469 

lb/gal N/A N/A Y 

0.0469 

lb/gal 

Household/domestic dwellings (indoor and 

outdoor) 

EC 

Lowpressure 

handwand 2.17E-04 

lb sq. ft 

N/A N/A Y 

PRL Aerosol 

can 

0.5% ai N/A N/A N 

Meat processing plant premises (nonfood 

contact) EC 

Lowpressure 

handwand 

0.0469 

lb/gal N/A N/A Y 
Chlorfenapyr Registration Review Human-Health Assessment Scoping Document 

Page 26 of 31 

Summary of Representative Occupational Use Patterns, Formulations, and Application Rates for Chlorfenapyr. 

Scenario covered? 

Crop / Site Formulationa Application 

Equipment 

Maximum 

application 

rates Mixer/ 

loader Applicator M/L/Ab 

Foam 

applicator 

0.0234 

lb/gal 

0.0234 

lb/gal Handpressure 

sprayer 

0.0094 lb 

linear ft 

Injection 

equipment 

0.0234 

lb/gal 

0.0234 

lb/gal Lowpressure 

handwand 1.09E-04 

lb sq. ft 

Lowvolume 

sprayer 

0.0023 lb 

sq. ft 

0.0234 

Power lb/gal 

sprayer 0.0094 lb 

linear ft 

Nonagricultural outdoor 

buildings/structures EC 

Pump 

spray 

0.0094 lb 

linear ft 

N/A N/A Y 

Ornamental and/or shade trees Liquid 

Highpressure 

handwand 

0.3215 

lb/100 gal N/A N/A N 

Pepino (melon pear) (greenhouse) SCc 

Highpressure 

handwand 

0.20 lb 

ai/A N/A N/A Y 

Pepper (greenhouse) SCc 

Highpressure 

handwand 

0.20 lb 

ai/A N/A N/A Y 

PRL Aerosol 

can 

0.5% ai N/A N/A N 

Poultry processing plant premises (nonfood 

contact) EC 

Lowpressure 

handwand 

0.0469 

lb/gal N/A N/A Y 

PRL Aerosol 

can 

0.5% ai N/A N/A N 

Sewage systems 

EC 

Lowpressure 

handwand 

0.0469 

lb/gal N/A N/A Y 

Tomatillo (greenhouse) SCc 

Highpressure 

handwand 

0.20 lb 

ai/A N/A N/A Y 

Tomato (greenhouse) SCc 

Highpressure 

handwand 

0.20 lb 

ai/A N/A N/A Y 
Chlorfenapyr Registration Review Human-Health Assessment Scoping Document 

Page 27 of 31 

Summary of Representative Occupational Use Patterns, Formulations, and Application Rates for Chlorfenapyr. 

Scenario covered? 

Crop / Site Formulationa Application 

Equipment 

Maximum 

application 

rates Mixer/ 

loader Applicator M/L/Ab 

PRL Aerosol 

can 

0.5% ai N/A N/A N 

Zoos 

EC 

Lowpressure 

handwand 

0.0469 

lb/gal N/A N/A Y 

a. PRL = pressurized release liquid; EC = emulsifiable concentrate. 

b. M/L/A = mixer/loader/applicator. 

c. HED assumes the product Chlorfenapyr SC (assessed in D288704) to be similar in formulation and application to 

Pylon, the product listed for use on these sites in BEAD’s Label Data Report. 
Chlorfenapyr Registration Review Human-Health Assessment Scoping Document 

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Attachment 5: Chlorfenapyr International Residue Limit Status 

Summary of US and International Tolerances and Maximum Residue Limits (01/14/2009). 

US Canada Mexico2 Codex 

Residue Definition: 

40CFR§180.513

chlorfenapyr [4-bromo-2-(4-chlorophenyl)-1-

(ethoxymethyl)-5-(trifluoromethyl)-1Hpyrrole-3-carbonitrile]

None chlorfenapyr None 

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) 

Commodity US1 Canada Mexico2 Codex

Vegetable, fruiting, group 8 1.0 1 

tomato 

Section 18 Emergency Exemption 

none 

Tolerances with Regional Registrations 

none 

Indirect or Inadvertent Residues

none 

Non-US MRLs with no US Equivalent 

Cotton seed 0.5 

1 (2) A tolerance of 0.01 parts per million is established for residues of chlorfenapyr in or on all food commodities 

(other than those covered by a higher tolerance as a result of use on growing crops) in food/feed handling areas 

where food/feed products are prepared, held, processed, or served and in accordance with the following prescribed 

conditions: 

(i) Application shall be no greater than a 0.5% active ingredient solution for spot crack and crevice use in food/feed 

handling establishments, where food and food products are held, processed, prepared and/or served. 

(ii) Application may only be undertaken when the facility is not in operation, and provided exposed food has been 

covered, or removed from the area being treated prior to application. 

(iii) Food contact surfaces and equipment should be thoroughly [sic] washed with an effective cleaning compound, 

and rinsed with potable water after each use of the product. 

(iv) Contamination of food or food contact surfaces shall be avoided. Application excludes any direct application to 

any food, food packaging, or any food contact surfaces. 

(v) To assure safe use, the label and labeling shall conform to that registered by the U.S. Environmental Protection 

Agency, and it shall be used in accordance with such label and labeling. 

2

 Information for Mexico is dated. Mexico adopts US tolerances and/or Codex MRLs for its export purposes. 
Chlorfenapyr Registration Review Human-Health Assessment Scoping Document 

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Attachment 6: DCI Justification for Dermal Studies 

Guideline Number: 870.3200 

Study Title: 21/28-Day Dermal Toxicity 

Rationale for Requiring the Data 

The 21/28-day dermal toxicity study is a new data requirement under 40 CFR Part 158 as a part of the 

data requirements for registration of a pesticide for food uses. 

The dermal toxicity Test Guideline (OPPTS.870.3200) is intended to evaluate the toxic effects associated 

with continuous or repeated exposures to a test substance for a period of 21/28-days. 

The Agency needs a 21/28-day dermal toxicity study for food use pesticides because the dermal route 

will be a primary route of exposure for chemicals designated with this use pattern. 

Practical Utility of the Data 

How will the data be used? 

A route specific (i.e., dermal) study will provide critical scientific information needed to characterize 

potential hazard to the human population exposed to the pesticide by the dermal route. This study will 

provide a dose and a toxicological endpoint of concern for quantification of risks for dermal exposures. 

This study would eliminate the uncertainties associated with the use of an oral study with a default (100% 

oral equivalent) dermal absorption factor. 

In many cases, toxicity observed via the dermal route will be different than toxicity observed via oral 

exposure, due to absorption and distribution of the toxic agent after exposure or differences in 

metabolism (i.e., systemic versus local). This means that the route-to-route extrapolation (i.e., use of an 

oral dose/endpoint) in risk assessment could result in under or over estimation of risks from the dermal 

route. 

How could the data impact the Agency’s future decision-making? 

If the dermal toxicity study indicates that the test material poses either a greater or lesser risk than that 

calculated using an oral dose, (as used in the interim decision), the risk assessment would be revised to 

reflect the magnitude of potential risk derived from the new data. Also, the requested data would allow 

the Agency to determine if the risks were over-estimated or under-estimated. If the risks were underestimated, additional risk mitigation measures could be required. If the risks were over-estimated, risk 

mitigation measures could be reduced. 

 
Chlorfenapyr Registration Review Human-Health Assessment Scoping Document 

Page 30 of 31 

 

Attachment 7: DCI Justification for Inhalation Studies 

Guideline Number: 870.3465 

Study Title: 90-Day Inhalation Toxicity Study 

Rationale for Requiring the Data 

A 90-day inhalation study is required under 40 CFR Part 158 (October 26, 2007) "if there is the 

likelihood of significant repeated inhalation exposure to the pesticide as a gas, vapor, or 

aerosol". 

Because only short- and intermediate-term occupational exposure durations are expected, a 

modified inhalation toxicity study (28-day timeframe) would be acceptable to assess risk 

through the inhalation route. If the registrant wishes to perform a 28-day rather than the 

standard 90-day inhalation toxicity study, they should submit a protocol and consult with the 

Agency prior to initiating the study to ensure the study design is acceptable.

Practical Utility of the Data 

How will the data be used? 

Repeated-exposure inhalation toxicity studies provide critical scientific information needed to 

characterize potential hazard to the human population on the effects of a pesticide from 

inhalation exposure. Since epidemiologic data on the effects of inhalation exposure to 

chlorfenapyr are unavailable and therefore inadequate to characterize a pesticide’s potential 

effects in humans, animal studies are used as the most sensitive endpoint for risk assessment. 

These animal studies can be used to select endpoints and doses for use in risk assessment of all 

exposure scenarios and are considered a primary data source for reliable reference dose 

calculation. 

How could the data impact the Agency's future decision-making? 

If the inhalation study shows that the test material poses either a greater or a diminished risk 

than that using the biomonitoring data in conjunction with the oral endpoint, then the risk 

assessments for the test material may need to be revised to reflect the magnitude of potential risk 

derived from the new data. If the Agency does not have this data, a 10X database uncertainty 

factor may be applied for conducting a risk assesment from the available studies. 
Chlorfenapyr Registration Review Human-Health Assessment Scoping Document 

Page 31 of 31 

Attachment 8: DCI Justification for Immunotoxicity Studies 

Guideline Number: 870.7800 

Study Title: Immunotoxicity

Rationale for Requiring the Data 

This is a new data requirement under 40 CFR Part 158 as a part of the data requirements 

for registration of a pesticide (food and non-food uses). 

The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional 

immunotoxicity testing and is designed to evaluate the potential of a repeated chemical 

exposure to produce adverse effects (i.e., suppression) on the immune system. 

Immunosuppression is a deficit in the ability of the immune system to respond to a 

challenge of bacterial or viral infections such as tuberculosis (TB), Severe Acquired 

Respiratory Syndrome (SARS), or neoplasia. Because the immune system is highly 

complex, studies not specifically conducted to assess immunotoxic endpoints are 

inadequate to characterize a pesticide’s potential immunotoxicity. While data from 

hematology, lymphoid organ weights, and histopathology in routine chronic or subchronic 

toxicity studies may offer useful information on potential immunotoxic effects, these 

endpoints alone are insufficient to predict immunotoxicity. 

Practical Utility of the Data 

How will the data be used? 

Immunotoxicity studies provide critical scientific information needed to characterize 

potential hazard to the human population on the immune system from pesticide exposure. 

Since epidemiologic data on the effects of chemical exposures on immune parameters are 

limited and are inadequate to characterize a pesticide’s potential immunotoxicity in 

humans, animal studies are used as the most sensitive endpoint for risk assessment. These 

animal studies can be used to select endpoints and doses for use in risk assessment of all 

exposure scenarios and are considered a primary data source for reliable reference dose 

calculation. For example, animal studies have demonstrated that immunotoxicity in 

rodents is one of the more sensitive manifestations of TCDD (2,3,7,8-tetrachlorodibenzop-dioxin) among developmental, reproductive, and endocrinologic toxicities. 

Additionally, the EPA has established an oral reference dose (RfD) for tributyltin oxide 

(TBTO) based on observed immunotoxicity in animal studies (IRIS, 1997). 

How could the data impact the Agency's future decision-making? 

If the immunotoxicity study shows that the test material poses either a greater or a 

diminished risk than that given in the interim decision’s conclusion, the risk assessments 

for the test material may need to be revised to reflect the magnitude of potential risk 

derived from the new data. 

 

If the Agency does not have this data, a 10X database uncertainty factor may be applied 

for conducting a risk assessment from the available studies.