Chlorfenapyr Registration Review Human-Health Assessment Scoping Document

Page 2 of 31 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 Re gistration Review. HED considered the most recent human-health risk assessments for chlorfena pyr 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 th e oral route (Toxicity Ca tegory 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 centr al 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 th e pups at the mid-dose based upon pup deaths on postnatal day (PND) 1-4, and canni balization 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 re quired 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 assessm ents should include, in addition to the parent, two chlorfenapyr metabolites for ruminant meat byproducts and f our chlorfenapyr metabolites for poultry meat byproducts. The tolerance expressi on 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 commoditi es in the table below. Compliance with the tolerance levels specified below is to be dete rmined by measuring only chlorfenapyr, 4-bromo-2- (4-chlorophenyl)-1-(ethoxyme thyl)-5-(trifluoromethyl)-1 H -pyrrole-3-carbonitrile, in or on the commodity.”

The residue chemistry database is sufficient to support the current registrations. Livestock dietary burdens should be reassesse d to evaluate potential seconda ry residues of chlorfenapyr and its metabolites in/on livestock commodities due to consumption of feed items with chlorfenapyr residues resulting from the estab lished food/feed handling area use. Reference standards for three chlorfenapyr metabolites are cu rrently 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 expos ure 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 ne w dietary risk assessment is re quired which utilizes the most current version of the Dietary Exposure Evalua tion Model software with the Food Commodity Intake Database (DEEM-FCID TM ; version 2.03), does not include DEEM TM default processing factors (which are not appropria te for an food handling establishment (FHE) use as residues would be expected to be incurr ed 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 exposur e assessment should also evaluate potential secondary residues of chlorfenapyr and its me tabolites in/on livestock commodities due to consumption of feed items with chlorfenapyr residues resulting from the established food/feedChlorfenapyr Registration Review Human-Health Assessment Scoping Document

Page 3 of 31 handling area use. Estimated drinking wate r concentrations (EDWCs ) do not need to be incorporated into the dietary asse ssments as long as the existing or proposed uses of chlorfenapyr continue to not result in the cont amination of drinking water.

There is sufficient information available to a ssess 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 su rfaces, as well as to the seams, folds and edges of mattresses. Application is restricted to pest management professionals; therefor e, the only potential residential exposure is through pos t-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 reside ntial 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 ri sk assessment will need to be conducted once a revised residential post applica tion assessment is available.

There is sufficient information available to a ssess occupational handl er exposure and postapplication exposure. Two occupational handler scenarios will need to be assessed during Registration Review and in addition, several o ccupational 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 labele d 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 residu e limits (MRLs) established for chlorfenapyr. The U.S. and Mexican tolerance definitions are harmonized for re sidues of chlorfenapyr in/on commodities in fruiting vegetable crop group 8. Th ere is an MRL of 0.5 ppm for cotton seed in Mexico which has no U.S. equivalent tolerance. Mexico adopts U.S. to lerances and/or Codex MRLs for export purposes.

Introduction

HED has evaluated the status of the human heal th assessments for chlorfenapyr to determine whether sufficient data are available and whethe r 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 toxi city, exposure, and usage databases that have occurred since the last registration; and the most recently updated Agency science policy and risk assessment methodologies to dete rmine 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 curren tly 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 (i ncluding 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. Th ere is sufficient informationChlorfenapyr Registration Review Human-Health Assessment Scoping Document

Page 4 of 31 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 pl ants, meat, milk, and poultry is chlorfenapyr only. The permanent tolerance expression for al l commodities is in terms of parent only; however, chlorfenapyr dietary risk assessments should include, in addi tion to the parent, two chlorfenapyr metabolites for ruminant meat bypr oducts 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 cha nge the registration status from conditional to unconditional.

Data requirements and risk assessment upda tes required under regi stration review for chlorfenapyr are as follows:

• The following studies are required as sp ecified 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 fr om the established food/feed handling area

use.

• The tolerance expression for ch lorfenapyr needs to be update d to reflect current Agency policy: “Tolerances are established for residue s 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-(et hoxymethyl)-5-(trifluoromethyl)-1 H -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-FCID TM (2.03), does not include DEEM TM default processing factors (which ar e not appropriate for an FH E use as residues would be expected to be incurred after processing) or citrus processing factors, and includes tolerances for the currently registered us es 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 postapplica tion and occupational handler and postapplication assessment will be necessary. The revised residential assessment will need to include dermal and in cidental oral routes of exposure. TwoChlorfenapyr Registration Review Human-Health Assessment Scoping Document

Page 5 of 31 occupational handler scenarios will need to be assessed during Registration Review and in addition, several occupationa l 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 cu rrent labeled applica tion 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 chlorfena pyr 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. Chlo rfenapyr has moderate acute toxicity via the oral route (Toxicity Category II) and low acute toxicity (Toxicity Cate gory 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 su bchronic neurotoxicity st udy. After a review of the chlorfenapyr hazard database, RAB1 toxico logists observed that a chronic neurotoxicity study had been performed. Because this study repr esents 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 (m ales only) and mice (both sexes) induced neurohistological changes (vacuolar myelinopathy) in the white ma tter of the brain, spinal cord, and/or spinal nerve roots. The 80-week car cinogenicity study in mice exhibited a dose- and compound-related effect on the CNS (brain vacuoliza tion), 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 th e 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 sp inal nerve roots) in ma le 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 myelin opathy 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 di d not demonstrate a clear dose -response and did not affect clinical signs such as ataxia or locomotor activ ity, 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 studi es (both sexes). In an acute neurotoxicity study, the rats in the high-dose group exhibited some neurobeha vioral changes at functionalobservational-battery (FOB) tes ting 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 matern al 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. Emacia tion and decreased food efficien cy were also seen in the subchronic dog study. Body-weight decrements were also noted in the rat and/or mouse subchronic, chronic, and carci nogenicity studies, as well as in the developmental andChlorfenapyr Registration Review Human-Health Assessment Scoping Document

Page 6 of 31 reproduction studies. Changes in hematology paramete rs consistent with anemia were also noted in the subchronic and chronic toxi city/carcinogenicity rat studies.

The 2003 HIARC clarified, but did not change, the ambiguous 1996 cancer classification of “cannot be determined, suggestive” for chlorfena pyr. The HIARC indicated that, according to EPA’s July 1999 Draft Guidelines for Carcinogen Risk Assessment , the current classification category of “Suggestive Evidence of Carcinoge nicity, but Not Sufficient to Assess Human Carcinogenic Potential” was a bett er description of the intent of the 1996 Cancer Peer Review Committee.

There is no evidence (qualitative or quantitat ive) for increased susceptibility following in utero exposure in the developmental toxi city 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-w eight 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 ef fects were noted up to the highest dose tested.

In a rat metabolism study, fecal excretion was the major route of elimina tion (80% of recovered radioactivity), with low recoveries of the radioactive chlorfenapyr in urine and tissues, indicating limited absorption. Most of the ra dioactivity was eliminated with in 48 hours of dosing. Female rats had greater (about twice) rec overy of radioactivity in the car cass, blood, and fat at all doses than did males. Parent compound was the ma jor radioactive component found in excreta, accounting for approximately 40-70% of the ad ministered doses. Minor amounts of eight primary and conjugated metabolites and four unide ntified isolated components were detected, each at less than 10% of the dosed radioactivity. Liver and kidne y 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-a lkylated, 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 assessmen t was based upon policy developed in 2002. In 2008, the FQPA policy was revised and updated (s ee Hot Sheet #30). Under the current policy, previous uncertainty factors which were uti lized independently are now components of the FQPA safety factor. Since th e last risk assessment, an acc eptable DNT study was submitted and reviewed, and this study satisfies the data requirement for which a 10X UF DB (now called FQPA SF) was applied in the past. Despite the cha nge 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 chlorf enapyr, 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.Chlorfenapyr Registration Review Human-Health Assessment Scoping Document

Page 7 of 31 Endocrine Disruption

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain su bstances (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 effect s 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 a ny, 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 substanc e, and establish a dos e-response relationship between the dose and the E, A, or T effect.
Between October 2009 and February 2010, EPA is issui ng test orders/data call- ins for the first group of 67 chemicals, which contains 58 pe sticide active ingredients and 9 in ert ingredients. This list of chemicals was selected based on the potential fo r 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 know n or likely endocrine disruptors.
Chlorfenapyr is not among the gr oup of 58 pesticide activ e 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 issuin g 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 pes ticide registration

. Because the immune system is highly complex, studies not specifically conducted to assess immunotoxic endpoints are in adequate to characterize a pesticide’s potential immunotoxicity. While da ta from hematology, lymphoid organ weights, and histopathology in routine chroni c or subchronic toxicity studies may offer useful information on potential immunotoxic effects, these e ndpoints 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 chlo rfenapyr should be conducted (See Attachment 6). Once all data have been received and revi ewed, the chlorfenapyr Registration Review Team recommends that the points of departure and safe ty 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 a nd registration review; however, as specified in the ne w 40 CFR Part 158 data requirement s, 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 st udy 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.Chlorfenapyr Registration Review Human-Health Assessment Scoping Document

Page 8 of 31 Residue Chemistry

Chlorfenapyr, 4-bromo-2-(4-chlorophenyl )-1-(ethoxymethyl)-5-(trifluoromethyl)-1 H -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 cu rrently registered. There are no tolerances established for secondary residues in/on livesto ck commodities as a result of chlorfenapyr residues in livestock feed items.

HED has previously received petit ions for tolerances of chlorfen apyr residues in/on cotton, citrus (domestic and imported), head a nd leaf lettuce, broccoli, caulif lower, 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 establis hed 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 establis hment 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 chlorf enapyr in cattle ear tags.

The nature of the residue in plants and lives tock 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 pl ants proceeds via: 1) N-dealkylation of the parent compound; and 2) oxidation of th e dealkylated metabolite. The permanent tolerance expression for all commodities is in terms of parent only; however, chlorfenapyr dietary risk assessm ents 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 e xpression for chlorfenapyr needs to be updated to reflect current Agency policy: “Tolerances are established for residues of chlorfenapyr, including its metabolites and degrad ates, in or on the co mmodities in the table below. Compliance with the tolerance levels sp ecified below is to be determined by measuring only chlorfenapyr, 4-bromo-2-(4-chlor ophenyl)-1-(ethoxymethyl)- 5-(trifluoromethyl)-1 H

pyrrole-3-carbonitrile, in or on the commodity.”

Acceptable tomato and orange processing studie s have been submitted and reviewed (Memo, G. Kramer, 01-FEB-1996; D218766; Memo, G. Kr amer, 06-AUG-1996; D222004). The tomato processing study indicated that re sidues 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 fo r 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 chlorf enapyr concentrate in oil (70X) and dried pulp (2.4X) and are not expected to concentrate in an y citrus juice (<0.01X). The citrus processing data do not apply to the FHE tole rance on citrus and therefore shoul d not be used in the dietary assessment unless a separate tolerance is estab lished for chlorfenapyr residues in/on citrus.Chlorfenapyr Registration Review Human-Health Assessment Scoping Document

Page 9 of 31 A new dietary exposure assessment will need to be conducted which evaluates potential secondary residues of chlorfenapyr and its me tabolites 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 diet ary 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)-1 H-pyrrole3-carbonitrile and 4-bromo-2-(3-chlorophenyl )-5-trifluoromethylpyrro le-3-carbonitrile are current until 01-OCT-2016, 01-JAN-2015, and 01-OC T-2017, respectively. Reference standards for chlorfenapyr metabolites 2,3-dichloropropio nitriole (24270) and 2-chloroacrylonitrile (42637) expired on 01-MAY-2009 and the chlorf enapyr metabolite bromovinyl desbromo pyrrole (Z) is currently out of stock (pers onal 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 assessmen ts should include, in addition to the parent, two chlorfenapyr me tabolites for ruminant meat byproducts (CL 325,195 [2-pyrrolidine-3-carbonitrile, 2-(p-chloropheny l)-5-hydroxy-4-oxo-5-(trifl uoromethyl)-} and CL 322,250 [pyrrole-2-carboxylic acid, 3-bromo- 5-(p-chlorophenyl)-4-c yano-]) and four chlorfenapyr metabolites for poultry meat byproducts (CL 303,268 [pyrro le-3-carbonitrile, 4- bromo-2-(p-chlorophenyl)-5-(trifl uoromethyl)-], CL 325,195 [2-pyrro lidine-3-carbonitrile, 2-(pchlorophenyl)-5-hydroxy-4-oxo-5-(trifluorom ethyl)-], CL 152,835 [acetic acid, {[2-(pchlorophenyl)-3-cyano-5 -(trifluoromethyl)pyrrol-1-yl]met hoxy}-] and CL 325,157 [acetic acid, {[3-bromo-5-(p-chlorophenyl)-4-cya no-2-(trifluoromethyl)pyrrol-1- yl]). The residue chemistry database is sufficient to suppor t the current registrations.

The residue chemistry database is sufficient to support the current registrations. Livestock dietary burdens should be reassesse d to evaluate potential seconda ry residues of chlorfenapyr and its metabolites in/on livestock commodities due to consumption of feed items with chlorfenapyr residues resulting from the estab lished food/feed handling area use. Reference standards for three chlorfenapyr metabolites are cu rrently 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 expos ure assessments were conducted using the DEEM- FCID TM , Version 2.0, which incorporates consump tion 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 an alyses represented the chlorfenapyr residues with the published permanent and temporary tolerance values (sec tion 3 and 18, respectively) asChlorfenapyr Registration Review Human-Health Assessment Scoping Document

Page 10 of 31 listed in 40 CFR §180.513 at the time of the assessm ent. A residue of 0.01 ppm was entered for all commodities except for the commodities in fr uiting vegetable group 8 (1.0 ppm) and citrus oil (35 ppm). An assumption of 100% crop treated (%CT) was made. DEEM TM 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 th e 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 wa s included and translat ed to all citrus juices due to a previously pending imported ci trus 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 in stead 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 include d in the dietary exposure assessment unless additional use patterns and resp ective tolerances are establishe d. 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 contamin ation 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 popula tion-adjusted dose (aPAD) for females 13-49 years old at the 95 th exposure percentile and 8% of the aPAD fo r the general U.S. population. The chronic dietary exposure resulted in a ri sk estimate that was 35% of th e 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 expos ure 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 ne w dietary risk assessment is re quired which utilizes the most current version of DEEM-FCID TM (2.03), does not include DEEM TM default processing factors or citrus processing factors, and in cludes tolerances for the curren tly registered uses on greenhouse grown fruiting vegetable crop group 8 commoditie s and FHE only. The new dietary exposure assessment should also evaluate potential secondar y 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 ha ndling area use. EDWCs do not need to be incorporated into the dietary asse ssments as long as the existing or proposed uses of chlorfenapyr continue to not result in the c ontamination of drinking water.Chlorfenapyr Registration Review Human-Health Assessment Scoping Document

Page 11 of 31 Residential Exposure

Chlorfenapyr is registered for residential (indoor and outdoor) and medical (indoor) uses. The representative residential use patterns, appli cation rates and formula tions are provided in Attachment 3.

Residential Handlers There are currently no registered residential uses that permit resi dential handlers. There is a registered insecticide/termiticide use that allows fo r applications in residential sites, for example, surfaces beneath cabinets and sinks, windows, and mattress seams. However, in the October 2001 occupational/residential exposure assessm ent (Memo, M. Dow, 16-OCT-2001; D238777), it was stated that the label for review onl y allowed for application by Pest-Management Professionals.

Residential Post-Application HED has determined that there is potential for post-application e xposure 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 exposur e resulting from this use. In the October 2001 occupational/residential exposure assessm ent (Memo, M. Dow, 16-OCT-2001; D238777), a residential post-application exposure assessmen t was conducted; however, only post-application inhalation exposure was assessed. Since the va por pressure of chlorfenapyr is <1.0 x 10 -7 mmHg at 25C°, HED did not expect si gnificant post-application inhala tion 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 assu mptions resulted in margins of exposure (MOEs) ≥ levels of concern (LOC = 100), expos ures did not exceed HED’s level of concern and are considered to be negligible.

Conclusions Residential handler exposure is not permitted by th e registered labels and is not expected. There is sufficient information available to assess re sidential post-applicati on exposure from treated dwellings. A revised residential post application assessment is necessary for the crack/crevice and mattress applications to account for possible de rmal and incidental oral exposures. HED is currently revising Residential Standard Operatin g Procedures (SOPs), including those used to determine exposure associated with crack and crevice and mattress treatments. Reviewers should incorporate new guidance from the update d SOPs to refine exposure estimates.

Aggregate Risk Assessment

Because there were no existing or proposed us es 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 as sessment 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 site s (including sewers), and indoor medical sites. A summaryChlorfenapyr 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 chem ical-specific data were available with which to assess potential exposure to pes ticide handlers. Therefore, o ccupational handler assessments were based primarily on surrogate unit expos ures from the Pesticide Handler's Exposure Database (PHED) as presented in the PHED Surr ogate Exposure Guide. The risk calculations were based on the maximum app lication rates and assuming ma ximum area treated per day or gallons handled. Handler's exposure and risk we re calculated at two levels of mitigation: baseline (long pants, a long-sl eeved shirt, no chemical-resistan t gloves, and no respirator) and personal-protective equipment (PPE; baseline clothing with chemical-resistant gloves when necessary). The representative occupational hand ler 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 ha ndlers used label prescribed PPE (i.e., long pants, long-sleeved shir t, shoes + socks, and protective glove s), all assessed MOEs were not of concern to HED (i.e., MOEs were ≥ LOC = 100) at the maximum labe l 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 maximu m 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 b een 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 maxi mum label rate of 0.32 lb ai/100 gal.

Conclusions There is sufficient information avai lable to assess occupational ha ndler exposure. In addition to those scenarios that have not been assessed pr eviously, several occupa tional handler scenarios may need to be reassessed if changes are made to the hazard assessment.

Occupational Post-Application Occupational post-application expo sure is expected from the fo liar uses of chlorfenapyr in greenhouses. Occupational post-application exposu re is not expected from the termiticide and crack and crevice use in residential sites, i ndoor 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 av ailable with which to estimate post-application exposure of agricultural workers to dislodgeable residues of chlo rfenapyr. HED does not expect significant post-application inhala tion exposure since the vapor pre ssure of chlorfenapyr is <1.0 x 10 -7 mmHg. Post-application dermal exposure ha s been estimated using an HED procedure that assumes 20% of the applicati on rate is available as dislodgeab le foliar residue on the day of treatment. The HED Science Advisory C ouncil for Exposure (ExpoSAC) Policy 003.1 lists a number of possible post-applicati on agricultural activities relative to some of the subject crops that result in potential pes ticide exposure to oc cupational 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-applicati on 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 follo wing post-application activities for fruiting vegetables were assessed: hand harv est, pruning, staking, th inning, training, tying, scouting, and weeding. MOEs were not of concern to HED (i.e., MOEs were ≥ LOC = 100). Assessment of post-application inhalation expo sure was deemed unnecessary due to the low vapor pressure of chlorfenapyr. Post-applica tion 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 asse ss occupational postapplication exposure. In addition to the aforementioned revisions, the oc cupational post applica tion exposure assessment may need to be reassessed if there ar e changes to the hazard assessment.

Public Health and Pesticide Epidemiology Data

A summary report listing incidents for chlorfena pyr 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 o ccurring in the U.S. from 2002 to the present.

Human Incident Data: OPP IDS (2010) For this evaluation, both the O PP 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 Occupati onal Risk-Pesticides (SENSOR) database were consulted for pesticide incident data on the ac tive ingredient chlorfenapyr. Additionally, the Agency is looking to include findings from the Agricultural Health Stud y (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 se verity of the health effects attributed to chlorfenapyr exposure.

The IDS includes reports of alle ged human health incidents fr om various sources, including mandatory Federal Insecticide, Fungicide and Ro denticide Act (FIFRA) Section 6 (a) (2) reportsChlorfenapyr Registration Review Human-Health Assessment Scoping Document

Page 14 of 31 from registrants, other federal and state hea lth 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 pr oduct information recorded. Reports submitted to the IDS represent anecdotal reports or allegations only, unless otherw ise stated in the report. The NIOSH SENSOR database covers 12 states from 1998-2006, although re porting varies from state to state (the database in cludes 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 physic ians suspecting pesticide exposure. Although both occupational and non-occupati onal 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 en ter the incident interview description provided by the worker, medical report, physician and patien t into the SENSOR data system, accessible to participating states and EPA.

The AHS is a high quality, prospective epidemio logy study evaluating the link between pesticide use and various health outcomes including cance r. The AHS includes private and commercial pesticide applicators and their spouses. If there are AHS findi ngs relevant to a particular pesticide going through registration review, the Ag ency will ensure they are considered in the problem formulation/scoping phase of the process a nd, if appropriate, fully reviewed in the risk assessment phase of the process. The AHS incl udes information on use of 50 different pesticide active ingredients commonly us ed in agriculture.

For IDS, HED identified two incidents occurring in the United States from 2002 to the present for the single chemical (chlorfenapyr) only. On e incident involved a person who experienced occupational exposure to his eyes while at wor k. The patient immediatel y flushed his eyes and the itchiness went away within few hours. The other case involved a patie nt with a history of brain surgery who developed seizures after be ing 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 exposu re 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 th erefore was not considered in the human incident report.

Conclusions Based on the low severity and low number of inci dent 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 con cern 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. Th ere is an MRL of 0.5 ppm for cotton seed in Mexico which has no U.S. equivalent tolerance. Mexico adopts U.S. to lerances and/or Codex MRLs for export purposes.

Environmental Justice

Potential areas of environmental ju stice concerns, to the extent po ssible, were considered in the human-health risk assessment, in accordance w ith U.S. Executive Order 12898, “Federal Actions to Address Environmental Just ice in Minority Populations an d Low-Income Populations,” (http://www.hss.energy.gov/nuclearsafety/env/ guidance/justice/e o12898.pdf). The OPP typically considers the highest potential exposures from the le gal 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 diet s within the U.S., and people who may be exposed when harvesting crop s. Should these highest exposures indicate potential risks of concern, OPP further refines th e risk assessments to ensure that the risk estimates are based on the best available information.

Human Studies

Past chlorfenapyr risk assessmen ts rely in part on data from studies in which adult human subjects were intentionally exposed to a pest icide to determine their dermal and inhalation exposure. Many such studies, i nvolving exposure to many different pesticides, comprise generic pesticide exposure databases such as the Pestic ide 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 uneth ical nor significantly de ficient relative to standards of ethical research conduct prevai ling when they were conducted. There is no regulatory barrier to continued reliance on these studies, and a ll applicable requirements of EPA’s Rule for the Protection of Human Subject s of Research (40 CFR Part 26) have been satisfied.

Data Requirements and Risk Assessment Upda tes 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 hi stopathological evaluation. Histopathology was not performed on the minimum number of tissues as set forth in the guidance (870.3200), including brain tissu e. Although the study was previously considered Acceptable, based on a re-evalu ation 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-toxic ity study in the rat, not the rabbit, which should include a full histopathological examinat ion, 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 rout e. 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 fr om the established food/feed handling area

use.

• The tolerance expression for ch lorfenapyr needs to be update d to reflect current Agency policy: “Tolerances are established for residue s 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-(et hoxymethyl)-5-(trifluoromethyl)-1 H -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-FCID TM (2.03), does not include DEEM TM default processing factors (which ar e not appropriate for an FH E use as residues would be expected to be incurred after processing) or citrus processing factors, and includes tolerances for the currently registered us es 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 postapplica tion and occupational handler and postapplication assessment will be necessary. The revised residential assessment will need to include dermal and in cidental 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 cu rrent labeled applica tion rates and updated transfer coefficients and may also need to be reassessed in accordan ce 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 Chroni c Dietary Exposure Analyses. Chemical#: 129093. DP Barcode: D257550. Case #: 287432. Submission #: S563946.

R. Cook D226458 21-NOV1996 PP6F4716. Chlorfenapyr on Potato es, 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 Pestic ide 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 Termitic ide-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 th e 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 Eff ects 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. Ch lorfenapyr 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 Divisi on (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 In secticide 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 Tomato es/Lettuce/Cabbag e/Potatoes. Barcode D227383. CBTS# 17304.

J. Tyler D279174 19-FEB2003 Chlorfenapyr. Acute and Chronic Dietary Exposure Assessments for Requests for Tolerances on Fruiting Ve getables 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 Gr eenhouse and Shadehouses.

Attachments

Attachment 1: Chemical Identity TablesChlorfenapyr 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 Pattern s/ Exposure Scenarios for Chlorfenapyr Attachment 5: Chlorfenapyr International Residue Limit Status Attachment 6: DCI Justif ication for Dermal Studies Attachment 7: DCI Justification for Inhalation Studies Attachment 8: DCI Justificat ion for Immunotoxicity StudiesChlorfenapyr 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-1 H -pyrrole-3- carbonitrile CAS name 4-bromo-2-(4-chlorophenyl)-1-(ethoxymethyl)-5-(trifluoromethyl)-1 H -pyrrole-3- carbonitrile CAS registry number 122453-73-0 Registration Review Case No. 7419
Chemical Formula C 15 H 11 BrClF 3 N 2 O
Chemical structure

Physical and Chemical Prop erties 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 ac tive 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 K ow = 67,670 (log K ow = 4.83) at 25 ° C
pH 7.16; 1% aqueous slurry at 24 ° C Memo, G. Kramer et al. , 12- FEB-1998; D221320Chlorfenapyr 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 Assessments 1

. 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/daybased 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 averagebody 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

Page 22 of 31 Summary of Toxicological Doses and Endpoints for Chlorfenapyr Used in 2003 Human-health Risk Assessments 1

. 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 averagebody 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 averagebody 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 Assessments 1

. 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 adve rse-effect level, LOAEL = lowestobserved adverse-effect level, PAD = po pulation-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

Page 24 of 31 Attachment 3: Residential Exposure Table Summary of Representative Residential Use Patterns, Formulations and Application Rates for Chlorfenapyr. Scenario Covered? Crop / Site Formulation a Equipment Max App Rate Qty M/L/A Postapp. Residential post-application only (PCO applied)

PRL Aerosol can 0.5% ai Y N Household/domestic 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 Pattern s/ Exposure Scenarios for Chlorfenapyr

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

Scenario covered? Crop / Site Formulation a Application Equipment Maximum application
rates Mixer/ loader Applicator M/L/A b

PRL Aerosol

can 0.5% ai N/A N/A N Commercial storages/w arehouse 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) SC b Highpressure handwand 0.20 lb ai/A N/A N/A YChlorfenapyr Registration Review Human-Health Assessment Scoping Document

Page 25 of 31 Summary of Representative Occupational Use Patterns, Formulations, and Applicatio n Rates for Chlorfenapyr.

Scenario covered? Crop / Site Formulation a Application Equipment Maximum application
rates Mixer/ loader Applicator M/L/A b

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) SC b High
pressure handwand 0.20 lb ai/A N/A N/A Y

Groundcherry (strawberry tomato/tomatillo) (greenhouse) SC c 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 plan t premises (nonfood contact) EC Lowpressure handwand 0.0469 lb/gal N/A N/A YChlorfenapyr Registration Review Human-Health Assessment Scoping Document

Page 26 of 31 Summary of Representative Occupational Use Patterns, Formulations, and Applicatio n Rates for Chlorfenapyr.

Scenario covered? Crop / Site Formulation a Application Equipment Maximum application
rates Mixer/ loader Applicator M/L/A b

Foam applicator 0.0234 lb/gal 0.0234 lb/galHandpressure sprayer 0.0094 lb linear ft

Injection equipment 0.0234 lb/gal 0.0234 lb/galLowpressure handwand 1.09E-04 lb sq. ftLowvolume
sprayer 0.0023 lb sq. ft

0.0234 lb/gal Power
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) SC c Highpressure handwand 0.20 lb ai/A N/A N/A Y

Pepper (greenhouse) SC c 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) SC c Highpressure handwand 0.20 lb ai/A N/A N/A Y

Tomato (greenhouse) SC c Highpressure handwand 0.20 lb ai/A N/A N/A YChlorfenapyr Registration Review Human-Health Assessment Scoping Document

Page 27 of 31 Summary of Representative Occupational Use Patterns, Formulations, and Applicatio n Rates for Chlorfenapyr.

Scenario covered? Crop / Site Formulation a Application Equipment Maximum application
rates Mixer/ loader Applicator M/L/A b

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 D 288704) to be similar in formulation and application to Pylon, the product listed for use on thes e sites in BEAD’s Label Data Report.Chlorfenapyr Registration Review Human-Health Assessment Scoping Document

Page 28 of 31 Attachment 5: Chlorfenapyr In ternational Residue Limit Status

Summary of US and Internatio nal Tolerances and Maximum Re sidue Limits (01/14/2009). US Canada Mexico 2 Codex Residue Definition: 40CFR§180.513 chlorfenapyr [4-bromo-2-(4-chlorophenyl)-1- (ethoxymethyl)-5-(trifluoromethyl)-1 H

pyrrole-3-carbonitrile] None chlorfenapyr None

Commodity Tolerance (ppm) /Max imum Residue Limit (mg/kg) Commodity US 1 Canada Mexico 2 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 fo r residues of chlorfenapyr in or on all food commodities (other than those covered by a higher tolerance as a re sult 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 ingr edient 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 eff ective cleaning compound, and rinsed with potable water after each use of the product.

(iv) Contamination of food or food c ontact surfaces shall be avoided. Applica tion excludes any direct application to any food, food packaging, or any food contact surfaces.

(v) To assure safe use, the label and labeling shall confor m 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

Page 29 of 31 Attachment 6: DCI Justif ication 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 derm al toxicity study for food use pesticides because the dermal route will be a primary route of exposure for chem icals 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 critic al 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 concer n for quantification of risks for dermal exposures. This study would eliminate the uncertainties associated w ith 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 mate rial poses either a greater or lesser risk than that calculated using an oral dose, (as used in the inte rim 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-est imated 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 CF R Part 158 (October 26, 2007) "if there is the likelihood of significant repeated inhalation expo sure to the pesticide as a gas, vapor, or aerosol".

Because only short- and interm ediate-term occupational exposure durations are expected, a modified inhalation toxicity study (28-day ti meframe) would be acceptable to assess risk through the inhalation route. If the registrant wishes to pe rform 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 toxici ty studies provide critical scientific information needed to characterize potential hazard to the human population on the e ffects of a pesticide from inhalation exposure. Since epidemiologic da ta 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 th e most sensitive endpoint for risk assessment. These animal studies can be used to select endpoi nts and doses for use in risk assessment of all exposure scenarios and are cons idered a primary data source for reliable reference dose calculation.

How could the data impact the Ag ency'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 conjun ction with the oral e ndpoint, then the risk assessments for the test material may need to be revised to reflect the magn itude 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 Justificat ion for Immunotoxicity Studies

Guideline Number: 870.7800 Study Title : Immunotoxicity Rationale for Requiring the Data This is a new data requirement under 40 CFR Pa rt 158 as a part of the data requirements for registration of a pestic ide (food and non-food uses).

The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional immunotoxicity testing and is designed to eval uate 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 vira l infections such as tuberc ulosis (TB), Severe Acquired Respiratory Syndrome (SARS), or neoplasia . Because the immune system is highly complex, studies not specifically conduc ted to assess immunotoxic endpoints are inadequate to characterize a pesticide’s pot ential immunotoxicity. While data from hematology, lymphoid organ weights, and hist opathology in routine ch ronic or subchronic toxicity studies may offer useful informa tion on potential immunot oxic 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 informa tion needed to characterize potential hazard to the human population on the immune system from pesticide exposure. Since epidemiologic data on the effects of ch emical 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 endpoint s and doses for use in risk assessment of all exposure scenarios and are cons idered a primary data source for reliable reference dose calculation. For example, animal studies ha ve demonstrated that immunotoxicity in rodents is one of the more sensitive manifestations ofTCDD (2,3,7,8-tetrachlorodibenzop-dioxin) among developmental, reproduc tive, and endocrinol ogic toxicities. Additionally, the EPA has established an oral reference dose (RfD) for tributyltin oxide (TBTO) based on observed immunotoxici ty in animal studies (IRIS, 1997).

How could the data impact the Ag ency's future decision-making? If the immunotoxicity study show s that the test material pos es either a greater or a diminished risk than that given in the inte rim decision’s conclusion, the risk assessments for the test material may need to be revise d 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.