UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

MEMORANDUM

DATE: 5/01/13 OFFICE OF CHEMICAL SAFETY
AND POLLUTION PREVENTION

SUBJECT: Captan: Human Health Ri s k Seeping Document in Support of Registration
Review.

PC Code: 081301
Decision No.: 478164

Petition No.: N/ A
Risk Assessment Type: Seeping Document

TXRNo. :N /A

MRID No.: N/ A DP Barcode: 411433 Registration No.: 7042-1 Regulatory Action: Registration Review
Case No.: 0120

CAS No

. : 133-06-2

40 CFR: §180.103

Jessica Kidwell, Risk Assessor

## ~**~()** Ayaad Assaad, D.V.M., Ph.D., TOxico logis t

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## ;:J?~ Bonnie Cropp-KohlligianlC mist/Diejao:_**~XB,OS)lre** 

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## /.(or ed)\":e...**~** _{<- FROM:

James Scott Miller, ORE**,...__._~ /~**  Risk Assessment Branch

, Health Effects Division (7509P)

THROUGH: Elissa Reaves, Ph.D., Branch Chief

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## ~ RAB IV, Health Effec ts Division (7509P)

TO : Christina Scheltema, Chemical Review Manager

Trac y Perry, Team Lea der RMIB3, PRD (7508P)

EXECUTIVE SUMMARY

Attached is the Health Effects Division 's (HED) human health risk assessment seeping

document for cap tan conducted as part of the Registration Re view p rocess. The HED Registration Review Team has evaluated the most recent human health risk assessments and
databases for cap tan to d eterm ine the scope of the work necessary to support Registration

Review. The most recent human health risk assessments for captan were the 1999 Captan Reregistration Eligibility Decision (RED) document (EPA 738-R-99 -015) and the 2004

Amendment to the 1999 Captan RED.Captan/08130 1 Scoping Document

Cap tan (N-trichloromethylthio

- 4 -c yclohexene- 1 ,2

- dicarboximide) is a fw 1g icide that belongs to fungicide resistance group M4 according to the Fun g icide Resistance Action Committee (FRAC, 2012). Captan is a broad-spectrum fungicide with protectant and some curative activity. Captan

is registered for u s e on f ood crops incl uding f olia r uses on almon ds

, appl es, apricots, blueberries,
caneberries (including blackbe rri es , dewberries, and raspb e rr ies (bl ack

, red)), cherries, ginseng (considered non-food u se )

, gra pes , nectarine s, peaches, pears, plum s, an d strawberries

. It is also

used as a root dip and as a seed treat me nt for n ume rous crops, as well as, a postharvest fruit dip

on apples, cherries and pears.

Fur the rmore, captan is used on non food crops including ornan1enta l herbaceous plants, turf,

ornamental woody shrubs and vines

, ornamental trees, wood structure protection and greenhouse
soils. According to EPA 's most recent Label Use Information System (LUIS) report (dated

9 / 1 0/12), all of the previously regis ter ed antimicrobial uses of captan have been canceled; hence,

these former uses will no t be discussed further herein.

Captan is appli e d by broadcast

, che migat ion, dust and drip tTea tm ent to s oil

, an d as a spo t application trea tment. Furthermore

, water dispersible granules (WDG) and liquid tlowable

concentrates (LFC ) are used for foliar app lic at i on to food pl ant s and applied by aerial an d ground equip me nt (a ir bla st and grou n d bo om), while field grown ornam entals an d gol f course turf is trea t ed via ground boom equipment. These formulations may also be appli e d to greenhouse ornamentals, fruit (nut tr ees in ho me ga rd ens), dire ctly to the so i £ around pl ants in

gree nho uses us ing ha nd held equip m ent such as a backpack sprayer, low pres sw·e h an d wand

, and a garden hose-end sprayer. Wettable powders (WP), flowable concent r ates (FC)

, and dust
fo rmu lati ons may be applied t o seeds as a sltmy, a dus t, or di re ctly into pl ant er boxes

.

Captan is a member ofN-trihalomethylthio group of compounds which characteristically act on th e gastrointestinal (GI) tract of mammals. While the thiophosgene moiety may be implicated in

association wi th the GI tract tumor s, its exact mode of action is unclear. Because of rapid

detoxification of parent compound and high reactivity of thiophosgene metaboli te i t is unlik e ly

to cause a buildup of th ese chemicals in the body. The thiophosgene moiety, although short lived, can cause irr itation at various sites depending upon the route of exposure.

Captan has low acute oral

, dermal, and inhalation tox ici t y (Toxicity Categories III-IV) with the exception of eye irritation, which is Toxicity Category I due to the irritant nature of captan to

mucus membranes such as the eyes, esophagus, lungs and s tomach.

Page 2 of33Captan/081301 Scoping Document

Page 3 of 33 The short term exposure studies with captan , including a 21

- day dermal toxicity, a 90

- day inhalation as well as chronic oral toxicity studies, suggest the possibility that thiophosgene causes local irritation of the skin, squamous hyperplasia of larynx or lining of the GI tract depending upon the site the thiophosgene comes in contact with. Captan was previously
classified as a B2, "probable human carcinogen" and canc er risk was quantified using the linear ( Q 1 * ) methodology

. At the request of the Captan Task Force, EPA’s Cancer Assessment Review Committee (CARC) re

- evaluated captan in 2004 and changed the cancer classification to "Likely to be carcinogenic to humans f ollowing prolonged, high

- level exposures causing cytotoxicity and regenerative cell hyperplasia in the proximal region of the small intestine (oral exposure) or the respiratory tract (inhalation exposure), but not likely to be a human carcinogen at dose le vels that
do not cause cytotoxicity and regenerative cell hyperplasia." In addition, captan is "Not likely to
be carcinogenic to humans via dermal exposure route" due to the very low dermal penetration of
captan. Future quantification of cancer risk will be through a non

- linear (RfD) approach since there are sufficient data to ascertain the mode of action for the tumor response.

No qualitative or quantitative susceptibility was seen in the developmental hamster or rabbit
studies or in the 2

- generation reproduction study in rats. The HASPOC recommend ed , based on a WOE approach, that acute and subchronic oral neurotoxicity studies are not required for captan at this time (TXR No. 0056559). The FQPA Safety Factor ( SF) was reduced to 1X based on the completeness of the toxicology and the lack of residual uncertainties for pre/post natal toxicity.

T herefore, the Reference Dose (RfD) equals the population adjusted dose (PAD).

Previously assessed h ighly refined (Tier 3 ) acute

, chronic

, and cancer dietary exposure analyses were performed on food only. At the 99.9 th percentile, 36 % of the acute Population Adjusted Dose (PAD) was used for Females 13

- 50 years (the only population subgroup identified as
relevant for the acu te dietary endpoint), and less than 2% of the chronic PAD was used for the General U.S. Population and all other population subgroups. As noted above, due to the cancer

re

- classification

, quantification of dietary cancer risk for any future risk assessmen ts will be
based on a non

- linear risk assessment, and not a Q 1 * approach as used in the last risk assessment. Risks from potential exposure to captan residues of concern in drinking water from all sources
were evaluated by comparing Estimated Drinking Wate r Concentrations (EDWCs) against calculated drinking water levels of comparison (DWLOCs ). T he EDWCs for captan residues of concern in ground and surface water did not exceed the Agency’s calculated DWLOC values.

Residential handler exposures were previously assessed in the 1999 Captan RED for the garden
hose

- end sprayer, low pressure handwand, shaker can, solutions mixed in jars for root dip, bulb and seed treatment for planting, and a backpack sprayer for turf an d home gardens and re

evaluated in 2004. R esidential turf uses were removed from all captan labels, leaving only ornamentals and fruit trees as exposure scenarios for residential handlers . The combined dermal and inhalation Margin s of Exposures (MOEs) ran ged from 240 to over 100,000 and were not of

concern

. Cancer was assessed in the 1999 RED, h owever, due to the cancer reclassification ofCaptan/081301 Scoping Document

Page 4 of 33 captan, quantification of cancer risk will now be through a non

- linear (RfD ) approach for all exposure scenarios.

In the 1999 Captan RED

, residential post

- application dermal exposures were assessed for
ornamentals and turf and then re

- evaluated in 2004. For o rnamentals, MOEs ranged from 72 at Days after Treatment ( DAT ) 1 to 1,000 at DAT 14. In the 2004 assessment

, b ased on the currently registered maximum application rates to turf, MOEs were 20 and 25 for adults and toddlers, respectively. Furthermore, the Agency was concerned about toddlers exposed to captan
th rough residential uses on lawns, whereas t he MOE for tod dlers' hand

- to

- mouth contact from
residues on low

- growing plants was approximately 11. The MOE for toddlers' hand

- to

- mouth
contact from residues on turf was 2. To mitigate this risk , the technical registrants agreed to voluntarily cancel the use of captan on all turf, except for sod farms and golf courses. Lastly, MOEs for dermal exposure in treated gardens ranged from 2,000 to 45,500

.

In the 1999 Captan RED, the acute and chronic dietary (food and drinking water) and cancer aggregate risks were not of concern. Residential exposure from the use of captan around the
home d id not exceed the level of concern when aggregated with food and drinking water. Short

term aggregate risk estimates for dietary and residential uses (ornamental/fruit tree and a irless paint sprayer) ranged from 330

- 390, which were not of risk concern.

O ccupational h andler exposure was assessed in the 1999 RED using PHED as surrogate exposure data , then re

- evaluated in 2004

. In the 2004 revised assessment, m ost short

- and
interm ediate

- term risks to handlers u sing captan were above 100 , with MOEs rang ing from 240 to 43,000. However, mixing/loading wettable powders for aerial applications to typical field

cro ps (strawberries) was the most conservative scenario with a MOE of 41. MO Es for mixer/loader/applicators and flaggers ranged from 840 to 270,000

.

Furthermore, o ccupational handler exposure during on farm and commercial seed piece

treat ment for multiple activities established MOEs that ranged fro m 338 to 35,400 for a variety of new seed crops including previous assessed crops such alfalfa, cereal grains, cotton, soybeans, corn, potatoes, and vegetables. A MOE of 2,400 was calculated for on

- farm seed planters.

Occupational post

- a pplication exposure was also addressed in the 1999 Captan RED and in the

2004 Amendment concerning estimated post

- application/reentry exposure for workers entering
"Terrestrial

- Food" crops treated with captan

. The Captan Task Force submitted four exposure Dislodgeable Foliar Residue ( DFR ) studies represented by MRID numbers 40988601, 4098860 2 (strawberries), 40988603, 40985601 (grapes), and 40988604, 40966501 (peach). These crops were used as surrogates for all other crops to which captan can be foliar

- applied. Occupational

p ost

- application MOEs ranged from 54 (Grapes: 3 lb ai/acre) to 1,000 (1 lb ai/acre). In the 2004 revision, post

- application exposure to grapes and raspberries was revisited. MOEs ranged from
90 at DAT 0 for grapes to 400 at DAT 0 for rasp berries

.Captan/081301 Scoping Document

Page 5 of 33 Occ upation al p ost

- a pplication was also addressed in the 1999 RED concerning estimated post

application/reentry exposure for workers entering "Terrestrial

- Non Food" crops treated with
captan. For ornamentals and turf, MOEs ranged from 180 to 1,000

. In 2004, orname ntal post application expos u re was revisited and MOEs of 400 on DAT 1 w ere reported.Captan/081301 Scoping Document

Page 6 of 33 Introduction

HED has evaluated the most recent human health risk assessment s for captan to determine
whether sufficient data were available and to determine the scope of the work necessary to support Registration Review. HED has also considered updates to cap t an ’s toxicity, exposure and usage databases, and current Agency science policies and risk assessment metho d s.

Use Profile

Agricultural Use s : Captan is registered for use on food crops including foliar uses on almonds, apples, apricots, blueberries, caneberries (including blackberries, dewberries, and raspberries (black, red)), cherries, ginseng (considered non

- food use), grapes, nectarines, peaches, pears, plums, and strawberries. It is also used as a root dip and as a seed piece and seed treatment for

numerous crops and as a postharvest fruit dip on apples, cherries and p ears. Furthermore

, captan is used on non food crops including ornamental herbaceous plants; sod farm and golf course turf; ornamental woody shrubs and vines; ornamental trees; wood structure protection and greenhouse soils.

Captan is applied by via broadcast

, chemigation

, dust and drip treatment to soil

, and as a s pot application treatment. Furthermore, water dispersible granules (WDG) and liquid flowable concentrates (FLC) are used for foliar application to food plants and applied by aerial and ground equipment (air blast and ground boom), while field grown ornamen tals and golf course turf are treated via ground boom equipment. These formulations may also be ap plied to greenhouse ornamentals, fr uit (nut trees in home gardens), directly to the soil around plants in greenhouses using hand held equipment such as a bac kpack sprayer; low pressure hand wand, and a garden
hose

- end sprayer. Wettable powders (WP), flowable concentrates (FC), and dust formulations may be applied to seeds as a slurry; a dust, or directly into planter boxes.

T he 2004 assessment noted that the Restricted Entry Intervals ( REIs ) that were to be established

are: 12

- hours for seed treatment uses; 24

- hours for strawberries, almonds, apples, apricots, cherries, nectarines, plums/fresh prunes, and peaches; 3

- days (72

- hours) for blueberries, raspberrie s, blackberries, and grapes; 4

- days (96

- hours) for ornamentals, and 24

- hours for soil

treatments.

Residential Uses : Previous registrations al l owed use of captan on ornamentals , and fruit and nut

trees . Captan was also used on turf (golf courses, athletic fields, and for homeowner use ) , but in the 2004 revised RED, homeowner turf applications were removed from all labels.

Hazard Identification/Toxicology

Captan is a member of N

- trihalomethylthio group of compounds (also includes F olp e t) which characteristically act on the gastrointestinal (GI) tract

, lung and other mucous membranes. While thiophosgene moiety may be implicated in association with the GI tract tumors, its exactCaptan/081301 Scoping Document

Page 7 of 33 mode of action is unclear. Because of rapid detoxifica tion of parent compound and high reactivity of thiophosgene metabolite

, it is unlikely to cause a build

- up of these chemicals in the body.

In acute toxicity studies, captan is not toxic via the oral route, and has low toxicity via the dermal and inhalation routes. Captan is severely irritating to the eyes.

The thiophosgene moiety, although short lived can cause irritation at various sites d epending upon the route of exposure to c aptan. The short term exposure studies with captan, including 21

- day dermal toxicity, 90

- day inhalation as well as chronic oral toxicity studies , suggest that thiophosgene causes local irritation of the skin, squamo us hyperplasia of larynx or lining of the gastrointestinal ( GI ) tract depending upon the site it comes in contact with. Repeated dermal application of c aptan caused dermal irritation but minimal systemic effects such as decrease in body weig ht gain and foo d consumption. The dermal absorption study in rats indicates that

c aptan is minimally absorbed. A dermal absorption rate of 0.4% per hour was determined for

c aptan.

Signs of GI tract disturbance such as emesis were seen in a chronic dietary study with dogs. Anorexia and decreased food consumption was reported in pregnant rabb its gavaged with c aptan.
In a mouse carcinogenicity study, effects were more severe , consisting of gastric, duodenal and jejunal hyperplasia leading to benign and malignant duoden al/jejunum

- ileum tumors. The
incidence of these tumors also increased in a dose

- dependent manner. In 1988 , EPA classified
captan as a “B2

- probable human carcinogen” and cancer risk was quantified using the linear ( Q 1 * ) methodology ( TXR Nos. 0050246, 005 0247) . However, in 2004, the CARC re

- classified
captan as “Likely to be carcinogenic to humans following prolonged, high

- level exposures causing cytotoxicity and regenerative cell hyperplasia in the proximal region of the small intestine (oral exposure) o r the respiratory tract (inhalation exposure), but not likely to be a human carcinogen at dose levels that do not cause cytotoxicity and regenerative cell hyperplasia.” In addition, captan is “Not likely to be carcinogenic to humans via dermal exposure

rou te” due to the very low dermal penetration of captan. This decision was based on the following weight

- of

- evidence considerations: (i) The occurrence of adenomas and adenocarcinomas in the small intestine of male and female mice; (ii) Captan is not likely t o be genotoxic in vivo ; (iii) The weight

- of

- evidence suggests that captan induces small intestine tumors by a nongenotoxic mode of action involving cytotoxicity and regenerative cell hyperplasia that exhi bits a clear dose threshold (TXR No. 0052869)

. Future quantification of cancer risk will be through a non

- linear (RfD) approach since there are sufficient data to ascertain the mode of action for the tumor response. This is different from the linear Q 1 * approach used in the previous risk assessments.

There was no qualitative or quantitative susceptibility seen in the developmental hamster and
rabbit studies or in the 1

- and 3

- generation reproduction studies. Studies in hamsters and rabbits showed that developmental and reproductive toxicity occurs on ly at or above doses that causeCaptan/081301 Scoping Document

Page 8 of 33 toxicity to parental animals. In a prenatal developmental toxicity study in hamster, developmental effects including delayed ossification and post

- implantation loss occurred at doses higher than those that produced decrease d body weight gain and mortality in maternal
animals. In the rabbit developmental toxicity study, increases in skeletal defects (27 pre

- sacral vertebrae) were noted at the same dose that caused body weight gain and food consumption
decrements in does. At doses that are toxic to the parent, captan causes decreased pup litter weights in a reproduction study. In one

- and three

- generation reproduction studies in rats, pups and parental animals were equally sensitive because body weight decreases were noted i n both at the same dietary dose levels

.

The Agency previously established toxicological endpoints for acute and chronic dietary, as well as occupational and residential (dermal and inhalation) exposure risk assessments for captan.
The de velopmental toxic ity study in rabbits with a developmental NOAEL of 10 mg/kg/day was
selected for the Acute D ietary endpoint for females 13

- 50 years old, as well as for the short

- and
intermediate

- term dermal endpoints, and for the inhalation endpoints (all durations). Thi s endpoint was selected because the observed developmental effects could occur following a single exposure, however, since these effects can occur only in utero, they are applicable only to
females of childbearing age, 13

- 50 years old

. The developmental LO AEL of 30 mg/kg/day was based on increased skeletal defects (27 pre

- sacral vertebrae) in fetuses. For the Acute dietary exposure scenario for females 13

- 50 years old, the acute PAD was 0.1 mg/kg/day. No separate acute dietary endpoint was selected for the general population. The 21

- day dermal toxicity study
in rabbits was not selected for the dermal risk assessments, even though it is the most appropriate route of exposure. In this study, repeated dermal application of captan caused dermal irritation, but only minimal systemic effects (reductions in body weight, body weight gain, and food consumption ) at a dermal dose of 1000 mg/kg/day, with a systemic NOAEL of 110 mg/kg/day. However, effects on fetuses are not investigated in a guideline 21

- day dermal toxicity study. Thus, because of the potential for occupational or residential dermal exposure to pr egnant women, the more conservative NOAEL from the oral developmental toxicity study in rabbits was considered appropriate for the short

- and intermediate

- term dermal risk assessments. Since an oral study was selected, a dermal absorption factor of 0.4% wa s used. A three generation reproduction study in rats was selected for the chronic dietary endpoint. The NOAEL in the study was 12.5 mg/kg/day based on decreased mean litter weights at the LOAEL of 25 mg/kg/day. For the chronic dietary exposure scenario, the chronic PAD was 0.13 m g /kg/day.

Toxicity Data Requirements

The toxicology data base is complete , with the exception of i mmunotoxicity data . In accordance with the 2007 revised 40 CFR Part 158 toxicology data requirements, a neurotoxicity battery and an immunotoxicity study would be required for captan. However, o n January 17, 2012, the

HASPOC , based on a weight of evidence a pproach , concluded that the acute and subchronic oral neurotoxicity studies are not required for captan at this time (TXR No. 0 056559)

. The HASPOC considered all the available hazard and exposure information for captan, including: (1) the lackCaptan/081301 Scoping Document

Page 9 of 33 of neurotoxicity in the available toxicity studies for captan; ( 2) the known target organs of captan

are mucus membranes such as the eyes, esophagus, lungs

, and stomach ; (3) the points of departure (PODs) used for risk assessments are protective of any potential irritation via the oral route and it is unlikely that neurotoxicity would be observed at a dose that is lower than the dose
that ca uses irritation via the oral route. Therefore

, the immunotoxicity study is the only outstanding data requirement. OPP has published the findings of an independent retrospective analysis 1 of 170 immunotoxicity studies submitted to the Agency. The retrospe ctive analysis suggest that the submitted immunotoxicity studies have not yet resulted in PODs that are lower than the PODs selected from other available guideline experimental toxicology studies. As a result, the currently available immunotoxicity studie s have not impacted the Agency’s risk assessments. HED is in the process of developing a guidance document on data waiver considerations. In the interim, HED recommends that immunotoxicity studies continue to be required for registration and registration r eview chemicals.

Hazard Conclusions

The toxicology database is adequate for risk assessment

. The PODs , e ndpoint s of concern

, and uncertainty factors for captan may need to be re

- evaluated during registration review to ensure
adherence to current policies and proce d ures. It is unlikely that an immunotoxicity study will yield a POD lower than those used in the existing human health risk assessments

.

Residue Chemistry

The residue chemistry database for captan is complete (D258267).

The nature of the residue in plants is adequately understood based on acceptable lettuce and tomato metabolism data. Captan is the major residue. Minor residues identified in the plant metabolism studies included 1,2,3,6

- tetrahydrophthalimide (THPI), cap tan epoxide, and THPI epoxide. Bis(trichloromethyl)disulfide, trans

- 3

- hydroxy

- 1,2,6

- trihydrophthalimide (3

- OH

THPI), and trans

- 5

- hydroxy

- 1,2,6

- trihydrophthalimide (5

- OH

- THPI) may also be present at very low levels. The residue of concern in plant commodi ties for tolerance enforcement is captan only. THPI should be included in the acute and non

- cancer chronic risk assessments (D258756)

. T his position may be confirmed by the Residues of Concern Knowledgebase Subcommittee (ROCKS) during r egistration r eview if needed.

The nature of the residue in livestock is adequately understood based on acceptable hen and goat metabolism data. No captan was detected in tissues, milk, or eggs. The major residues in goat muscle, liver, kidney, and milk were 3

- OH

- THPI a nd 5

- OH

- THPI. THPI was the major residue in goat fat and hen matrices. The residues of concern in livestock commodities for tolerance enforcement and risk assessment are captan and THPI.

1 http://www.epa.gov/pesticides/regulating/immunotoxicity

- retro

- analysis.pdfCaptan/081301 Scoping Document

Page 10 of 33 An adequate gas chromatographic (GC)/electron capture detectio n (ECD) enforcement method is available for enforcing tolerances of captan in/on plant commodities and is listed as Method I, in

PAM , Vol. II. Zeneca Method No. 166 for quantifying THPI in meat and milk has been
validated for use in tolerance enforcement. Other methods in PAM , Vol. II that use colorimetry to determine captan residues are no longer considered suitable for tolerance enforcement. Captan is completely recovered using FDA Multiresidue Protocols D (Luke Method; 232.4) and
E Section 211.1 for o ily matrices and partially recovered using FDA Multiresidue Protocol E
Section 212.1 for non

- oily matrices. THPI is completely recovered using FDA Multiresidue
Protocol D.

Tolerances are established under 40 CFR §180.103(a) for residues of captan (N

tric hloromethylthio

- 4

- cyclohexene

- 1,2

- dicarboximide) in/on almond; almond, hulls; apple; apricot; blueberry; caneberry, subgroup 13A; cherry, sweet; cherry, tart; grape; nectarine; peach; pear; plum, prune, fresh; and strawberry at 0.25

- 75.0 ppm to cover resid ues resulting from foliar and/or post

- harvest uses and in/on numerous other raw agricultural commodities at 0.05 ppm to cover residues resulting from seed treatment uses

. All the commodities and their respective tolerances are listed in the Appendix. Tol erances are established under 40 CFR §180.103(b) for residues of captan (N

- trichloromethylthio

- 4

- cyclohexene

- 1,2

- dicarboximide) and its metabolite 1,2,3,6

- tetrahydrophthalimide (THPI) in ruminant tissues at 0.15

- 0.30 ppm and in milk at 0.10 ppm. Since the re is no reasonable expectation of finite residues of concern in poultry and eggs, no tolerances for captan residues of concern have been established in these commodities. The tolerance expression will need to be updated in accordance with current policy.

Residue Chemistry Conclusions

The residue chemistry database is complete. The qualitative nature of captan residues in the registered crops and livestock is adequately understood based on acceptable metabolism studies.
The residue of concern in plant commodities for tolerance enforcement is captan only. The
residues of concern in livestock commodities for tolerance enforcement and risk assessment are captan and 1,2,3,6

- tetrahydrophthalimide (THPI). The captan tolerance expression will need to
b e updated in accordance with current policy. Adequate analytical enforcement methods are available. The combined residues of captan and are considered the total residue of concern for the purposes of acute and chronic non

- cancer dietary risk assessments; t his position may be confirmed by the Residues of Concern Knowledgebase Subcommittee (ROCKS) during registration review if needed.

Dietary Exposure and Risk

The combined residues of captan and 1,2,3,6

- tetrahydrophthalimide (THPI) are considered the total residue of concern for the purposes of acute and chronic non

- cancer dietary risk assessments (D258756 and 1999 Captan RED). This position may be confirmed by the Residues of Concern Knowledgebase Subcommittee (ROCKS) during r egistration r eview if n eeded.Captan/081301 Scoping Document

Page 11 of 33 For the purposes of chronic cancer dietary risk assessment, only captan is considered since the carcinogenicity of captan is believed to be associated with the reactive thiophosgene moiety.
The CARC re

- evaluated Captan in 2004 (TXR No. 0052869)

. Based on the new classification,

f uture quantification of cancer risk will be through a non

- linear (RfD) approach since there are sufficient data to ascertain the mode of action for the tumor response. This is different from the linear Q 1 * approach used i n the previous risk assessments.

Dietary Risk

The most recent dietary exposure assessments (D25240 5 and D259452) used the Dietary Exposure Evaluation Model (DEEMTM) software and consumption data from USDA’s Continuing Surveys of Food Intakes by Individua ls (CSFII), 1989

- 92. This dietary exposure assessment evaluated captan residues of concern in food but not drinking water. Highly refined (Tier 3) acute (D252404) and chronic cancer and non

- cancer (D259452) dietary exposure analyses were performed on foo d only. Anticipated residue estimates were based on field trial or monitoring data. Processing, washing, and cooking data to estimate reduction/concentration factors and percent crop treated data were also used when available. At
the 99.9 th percentile, 36 % of the acute Population Adjusted Dose (PAD) was used for Females

13

- 50 years (the only population subgroup identified as relevant for the acute dietary endpoint),
and less than 2% of the chronic PAD was used for the General U.S. Population and all othe r population subgro ups. Dietary cancer risk from captan was 1.3 x10 - 7 based on the Q 1 * for captan
of 2.4 x 10 - 3 (mg/kg/day) - 1

.

Drinking Water

Captan is expected to degrade relatively rapidly in the environment. However, there is a potential for the degradate THPI to reach ground and surface water due to application rates and multiple applications of captan. Risks from potential exposure to capt an residues of concern in drinking water from all sources was comprehensively discussed in the 1999 Captan RED and risks were
evaluated by comparing Estimated Drinking Water Concentrations (EDWCs) against calculated drinking water levels of comparison (DWL OCs).

The potential groundwater and surface water exposures to captan and THPI were assessed based on Tier 1 and Tier 2 models, respectively, which provide computer

- generated EDWCs. The
assessment in the 1999 Captan RED indicated that the EDWCs for ca ptan residues of concern in ground and surface water did not exceed the Agency’s calculated DWLOC values. [Note: Surface drinking water estimates used in the acute and chronic non

- cancer dietary risk
assessments in the 1999 Captan RED only included resid ue values for THPI but should have included residue values for captan as well. However, the combined EDWCs for captan plus
THPI in surface water do not exceed the DWLOC values in the 1999 Captan RED.] The Agency no longer relies on DWLOCs and drinking wa ter estimates may need to be updated for the dietary assessment.Captan/081301 Scoping Document

Page 12 of 33 Dietary Exposure and Risk Conclusions

HED has previously assessed dietary exposures and risks from these exposures were below the Agency’s level of concern. New acute and chronic dietar y risk assessments may need to be conducted using the newest version of the Dietary Exposure Evaluation Model DEEM

- FCID TM

, Version 3.16 which uses food consumption data from the U.S. Department of Agriculture’s

National Health and Nutrition Examination Sur vey, What We Eat in America, (NHANES/ WWEIA) and incorporate potential changes to the captan toxicological points of departure (PODs) and uncertainty factors. If new dietary risk assessments are conducted under r egistration review, updated percent crop tr eated data may be needed for dietary risk refinements. Since

CARC re

- evaluated Captan in 2004 (TXR No. 0052869) and captan has a new classification,

f uture quantification of cancer risk will be through a non

- linear (RfD) approach since there are
sufficien t data to ascertain the mode of action for the tumor response. This is different from the linear Q 1 * approach used in the previous risk assessments. The Agency no longer relies on DWLOCs and drinking water estimates may need to be incorporated directly into the dietary

assessments.

The most recent drinking water estimates are adequate based on current methodologies but may
need to be revised. EFED may wish to generate a single comprehensive drinking water assessment under registration review for the purposes of documentation. Surface drinking water estimates used in the most recent acute and chronic dietary risk assessments only included
residue va lues for THPI ( 1999 Captan RED) but should have included residue values for captan
as well. This should be corrected in the registration review risk assessment. [Note: The combined EDWCs for captan plus THPI in surface water do not exceed the Agency’s c alculated DWLOC values.]

Occupational and Residential Exposure

O ccupational handler exposure was assessed in the 1999 RED using PHED as surrogate exposure data , and then re

- ev a luated in 2004 (D305649). The exposure scenarios that were
assessed are as follows: aerial; groundboom; airblast; high pressure sprayer; low pressure handwand; commercial hose

- end and backpack sprayers; and seed and seed piece treatment. Furthermore, a post

- harvest dip assessment was conducted for apples, cherries, and pears as
well. Although exposure to c ommercial painter s applying paints containing captan was estimated for the RED, these products have since been removed from the market

.

The most recent human health risk assessment for captan was a 2004 amendment to the 1999 Captan RED document (EPA 738

- R

- 99

- 015) in support of a petition for the domestic use of captan on various agricultural crops and non agricultural crops; including seed treatment and residential gardens. Residential turf applications were removed from all labels.Captan/081301 Scoping Document

Page 13 of 33 Occupational Handler Results

In the 2004 revised assessment, m ost short

- and intermediate

- term risks to handlers u sing captan

were above 100

, the level of concern, with MOEs rang ing from 240 to 43,000. However, mixing/loading wettable powders fo r aerial applications to typical field cro ps (strawberries) was
the most conservative scenario with a MOE of 41. MOEs for mixer/loader/applicators and flaggers ranged from 840 to 270,000

. A cancer assessment was conducted in the 1999 RED,
however in 2004

, as stated above, due the cancer reclassification of captan, quantification of cancer risk will now be through a non

- linear (RfD) approach

.

According to the Guidance for Requiring/Waiving Turf Transferable Residue (TTR) and
Dis l odgeable Foliar Residue (DFR) Studies (Housenger , 2012 ), a calculated MOE of approximately 10 time higher than the level of concern (e.g., an MOE > 1,00 0 if the LOC = 100) using the default residue transfer values should provide an adequate margin of safety for any potentially hi gher residues seen in a chemical specific TTR study. In the case of c aptan, mixing and loading for sod farm use registers a combined MOE of 90, for single layer clothing, gloves
and a PF5 dust

- mist respirator, which is the label specific Personal Protecti ve Equipment ( PPE )

. Therefore, a TTR study will be needed for turf exposure uses.

PPE for captan applications was established on existing labels as; coveralls, chemical resistant glove, shoes plus socks, and protective eyewear, and a dust mist respirator for wettable powder
and dust formulations.

Occupational Handler: Seed and Seed Piece treatment

According to the 2004 Amendment to the 1999 Captan RED , o ccupational handler exposure during on farm and commercial seed piece treat ment for multiple activities established MOEs that ranged from 338 to 35,4 00 for a variety of seed crops

, including alfalfa, cereal grains, cotton, soybeans, corn, potatoes, and vegetables. A MOE of 2,400 was calculated for on

- farm seed planters.

A cance r assessment was conducted in the 1999 Captan RED and the 2004 Amendment using the Q 1 * approach. However

, the CARC re

- evaluated captan and changed the cancer classification as discussed in the toxicity section. Quantification of cancer risk will now be through a non

linear RfD approach since there are sufficient data to ascertain the mode of action for the tumor

response.

Occupational Post

- Application for Food Crops:

In the 1999 RED and the 2004 Amendment to the RED

, to address estimated post

applicati on/reentry exposure for workers entering crops treated with captan, the Captan Task
Force submitted four DFR exposure studies represented by MRID numbers 40988601,Captan/081301 Scoping Document

Page 14 of 33 40988602 (strawberries), 40988603, 40985601 (grapes), and 40988604, 40966501 (peach). The

C aptan Task Force used application rates that ranged from (1 lb ai/acre) to (3 lbs ai/acre). These three crops were used as surrogates for all other crops to which captan can be foliar

- applied.

Post

- application MOEs ranged from 57 at DAT 0 (Grapes: 3 lb ai /acre) to 1,000 at DAT 14 (Strawberries: 1 lb ai/acre).

T he post

- application MOEs were revisited for ornamentals, berries and grapes (D305649) . The MOEs ranged from 90 at “DAT 0” for grapes to 400 at "DAT 0 for berries."

Occupational Post

- Application for Non

- Food Crops:

Occupational p ost

- a pplication exposure was also addressed in the 1999 RED and supporting
documents (D222418, D226527) concerning estimated post

- application/reentry exposure for

wo r kers entering "Terrestrial

- Non Food" crops treated with captan. EPA a ssessed spray applications to azaleas; begonias; camellias; carnations; chrysanthemums; conifers; dichondra; gladiolus; grasses (lawns and lawn seedbeds); ornamental flowering plants, and roses. To calculate risk for workers harvesting and bundling flowers, EPA used DFR data from the Task Force's Strawberry DFR study (MRID 409886

- 01) and transfer coefficients developed in the Netherlands (Brouwer et al

. 1983 )

. Margin of Exposures (MOEs) f or occupational post

application exposure to ornamentals and turf ranged from 180 at DAT 1 to 1,000 at DAT 14

.

In the 1999 RED, a 48

- hour re stricted

- entry interval was established for captan, since the active ingredient is classified as toxicity category I for eye irritation potential.

T he 2004 assessment noted t he REIs that w ere established: 12

- hours for seed treatment uses; 24

- hours for strawberries, almonds, apples, apricots, cherries, nectarines, plums/fresh prunes, and peaches; 3

- days (72

- hours) for blueberries, raspberries, blackberries, and grapes; 4

- days (96

- hours) for ornamentals, and 24

- hours for soil treatments.

A quantitative post

- application inhalation exposure assessment was not performed for captan

. However, there are multiple potential sources of post

- application inhalation exposure to individuals performing various activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain

pe sticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on Mar ch 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The Agency is currently evaluating the SAP report. EPA is also evaluating the available post

- application inhalation exposure data generated by the Agricultural Reentry Task Fo rce and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate occupational post

- application inhalation exposure into the Agency's riskCaptan/081301 Scoping Document

Page 15 of 33 assessments. If new policies or procedures are put int o place, the Agency may revisit the need for a quantitative occupational post

- application inhalation exposure assessment for captan

.

Residential Handler :

In the 2004 revision to the 19 9 9 RED , residential turf applications were removed leaving only

orname ntals and fruit trees as exposure scenarios. The combined dermal and inhalation MOEs ranged from 240 to over 100,000 and were not of concern.

Residential Post

- application :

Ornamentals: Residential post

- application exposures were previously assessed in the 1999 RED for ornamentals and turf. For ornamentals, MOEs ranged from 72 at DAT 0 to 1,000 at DAT 14
and were not of concern.

Turf: In the 2004 assessment; based on the currently reg istered maximum application rates to turf, MOEs were 20 and 25 for adults and toddlers, respectively. Furth e rmore, the Agency was concerned about toddlers exposed to captan through residential uses on lawns. The MOE for
toddlers' hand

- to

- mouth contact from residues on low

- growing plants was approximately 11.
The MOE for toddlers' hand

- to

- mouth contact from residues on turf is 2. To mitigate this use, the technical registrants agreed to voluntarily cancel the use of captan on all turf, except for sod
farms a nd golf courses.

Spray Drift : Residential exposures resulting from off

- site transport (e.g., spray drift or volatilization) may occur as a result of applications for captan. The Agency is in the process of evaluating these types of exposures and will ex amine the need for spray drift and volatilization assessments for captan during registration review

Conclusions for Residential and Occupational Exposure Due to recent residential and occupational exposure science policy updates, existing residential
and occupational scenarios may have to be reassessed. These updates include changes to data sources and default assessment inputs for both handler and post

- application assessments. In addition, the assessment may need to be updated to reflect the carcinogeni city reclassification
and any potential changes to the PODs and uncertainty factors for captan.

Aggregate Exposure and Risk

In the 1999 Captan RED

, the acute and chronic dietary (food and drinking water) and cancer aggregate risks we re not of concern. Residential exposure from the use of captan around the
home d id not exceed the level of concern when aggregated with food and drinking water. Short

term non

- cancer aggregate risk estimates for dietary and residential uses (ornamental/fruit tree
and airless paint sprayer) ranged from MOEs of 330

- 390, which we re not of risk concern.Captan/081301 Scoping Document

Page 16 of 33 Based on a shared common metabolite, thiophosgene, and a cancer concern through the oral

route, a n aggregate cancer assessment was also conducted for combined dietary exposure s t o captan and folpet through the oral route

. The aggregate exposure from folpet and captan residues
in food and water did not exceed the EPA’s level of concern for cancer risk for the U.S. population

.

Public Health and Pesticide Epidemiology Data

Based on the low frequency and severity of incident cases reported for captan in both the OPP Incident Data Systems ( IDS ) and Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event Notifi cation System for Occupational Risk

- Pesticides (SENSOR) databases , there does not appear to be a concern at this time that would warrant further investigation (D409190). The Agency will continue to monitor the incident information and if a concern is trig gered, additional analysis will be included in the risk assessment. In addition, EPA will continue to review the literature regarding evidence of the carcinogenic potential of captan in the Agricultural Health Study ( AHS ) cohort.

Tolerances and International Harmonization

The U.S.

, CODEX

, and Canadian residue definitions for captan in/on plant commodities are harmonized. The U.S. has established tolerances in livestock commodities but there are no CODEX or Canadian MRLs established in any lives tock commodity. Mexico adopts U.S. tolerances and/or Codex MRLs for export purposes.

U.S. tolerance levels are not fully harmonized with CODEX and may need to be reassessed

. (See International Residue Limits table in the Appendix). Only the captan tole rances and CODEX
MRLs for blueberry, grape, plum, and potato (U.S. tolerance in/on Vegetable, root and tuber, group 1) are currently harmonized. None of the U.S. tolerances and Canadian MRLs are currently harmonized.

Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmen tal, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its r eregistration decision

, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazardCaptan/081301 Scoping Document

Page 17 of 33 database. However, as required by FFDCA section 408(p), captan is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the 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 b y the substance, and
establish a dose

- response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- in s for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. Captan was included on that list and has been issued an order to conduct the Tier 1 testing. Once all required Tier 1 and
Tier 2 data have been received and reviewed, the endpoints and safety factors used for risk assessment purposes will be examined and a new risk assessment performed if necessary. For further information on the status of the EDSP, the policies and procedures, the list of 67
ch emicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our
website: http://www.epa.gov/endo/

.

C umulative

Unlike other pesticides for which the EPA has followed a cumulative risk approach based on a common mechanism of toxicity, the EPA has not made a common mechanism of toxicity fin ding
as to captan or any other substances. Although folpet and captan share the common metabolite thiophosgene, its role in folpet’s and captan’s toxicity has not been determined because thiophosgene is transient and not easily measurable . Therefore, the EPA has not assumed that
captan has a common mechanism of toxicity with captan or any other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s OPP concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://ww w.epa.gov/pesticides/cumulative/

.Captan/081301 Scoping Document

Page 18 of 33 Human Studies

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from Standard Oper ating Procedures (SOPs) for Seed Treatment, Policy 14 , 15, and 15.1 are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review ma y have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at http://www.epa.gov/pesticides/science/ handler

- exposure

data.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html

.

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/nucle arsafety/env/guidance/justice/eo12898.pdf). 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 sourc es near agricultural areas, the variability of diets within the U.S., and people who might be exposed when harvesting crops. Should these highest exposures indicate potential risks of concern, OPP further refines the risk assessments to ensure that the ri sk estimates are based on
the best available information.

Data Requirements

Toxicology:

Guideline 870.7800 Immunotoxicity

Residue Chemistry: No data requirem ents

.

Occupational Exposu re (ORE) : Turf Transferable Residue ( TTR) data (Guideline 875.2100)

.

Residential Exposure (ORE ) : No data requirements

.Captan/081301 Scoping Document

Page 19 of 33 Risk Assessment Updates Required Under Registration Review

Hazard Conclusions: The toxicology database is adequate for risk assessment. The PODs , endpoints of concern and uncertainty factors may need to be re

- evaluated during registration review to ensure adherence to current policies and procedures

. It is unlikely that an immunotoxicity study will yield a POD lower than those used in the existing human health risk assessments

.
Dietary and Drinking Water Exposure and Risk : New acute and chronic dietary risk assessments may be needed if there are changes to
the captan toxicological PODs, uncertainty factors, or drinking water assessment. T he assessment may need to be updated to reflect the carcinogenicity reclassification

. If new dietary risk assessments are conducted under registration review, updated percent crop
treated data m ay be needed for dietary risk refinements.

Surface drinki ng wate r estimates used in the most recent acute and chronic non

- cancer dietary risk assessments only included residue values for THPI ( 1999 Captan RED ) but should have included the estimated residue values for captan as well. This should be corrected in the registration review risk assessment. [Note: The combined EDWCs for captan plus THPI in surface water did not exceed the Agency’s calculated DWLOC values.]

Residue Chemistry: The tolerance expression will need to be updated in accordance with current policy. The combined residues of captan and THPI are considered the total residue of concern for the purposes of acute and chronic non

- ca ncer dietary risk assessments; t his position may be confirmed by the Residues of Concern Knowledgebase Subcommittee (ROCKS) during registration review if needed.

Tolerances and International Harmonization: U.S. tolerance levels are not fully harmonized and may need to be reassessed for CODEX
harmonization.

Occupational and Residential Exposure (ORE) and Risk : The residential and occupational exposure asse s s m en t s may need to be updated to reflect
current SOPs and to incorporate any new endpoints or uncertainty factors selected based on the required toxicity and ORE studies.Captan/081301 Scoping Document

Page 20 of 33 References

1986. Engler, R. Peer Review of Captan, Caswell No. 159. 12/29/1986. TXR No. 0050246.

1987. Garbus, J. Product Chemistry Registration Standard. 2/2/87.

1988. Rinde, E. Peer Review (2 nd ) of Captan, Addendum. July 20, 1988. TXR No. 0050247.

1996. Mostaghimi, S. Recalculation of Captan EEC’s for Almonds, Apple, Peaches, Prunes,

Cherries and Blueberries. 6/28/96. D210410.

1997. Burnam, W. Captan Q1* Revisited. 10/6/1997. TXR No. 0051523.

1997. Evans, J. Revised Occupational and Residential Exposure Assessment for the Captan Reregistration Eligibility Decision (RED). D222418, D226527

.

1999. Maher. E F ED’s revisions to the EFED Captan RED chapter. 4/23/99. D253634.

1999. Piper, S. Reregistration Case No 0120. Tier 3 (Monte Carlo) Acute Dietary Exposure Estimates for Captan. 5/3/99. D252405.

1999. Morton, T. Reregistration Case No 0120. Produ ct and Residue Chemistry Chapters for the Captan Reregistration Eligibility Decision (RED). 8/3/99. D258267.

1999. Hrdy, D. Captan (N

- trichloromethylthio

- 4

- cyclohexene

- 1,2

- dicarboximide): HED Risk Assessment for the Registration Eligibility Decision (RED) Document. 8/11/99. D258756.

1999. Hrdy, D. Reregistration Case No 0120. Tier 3 Chronic Cancer and Non

- Cancer Dietary Exposure Estimates for Captan. 9/23/99. D259452.

1999. Captan Reregistration Eligibility Decision (RED). November, 1999.

2004. Captan: Fourth Report of the Cancer Assessment Review Committee. 9/22/04. TXR No.
0052869.

2004. Amend ment to the 1999 Captan RED. 11/1/04

.

2004. Hrdy, D. Captan (N

- trichloromethylthio

- 4

- cyclohexene

- 1,2

- dicarboximide): HED
Revisions to the Occupational Risk Assessment for the Reregistration Eligibility Decision (RED)

Document. Chemical No. 081301. Case No. 0120. D305649.Captan/081301 Scoping Document

Page 21 of 33 2012. Housenger, J. Guidance for Requiring/Waiving Turf Transferable Residue (TTR) and
Dis l odgeable Foliar Residue (DFR) Studies . 12/12/12.

2013. V an Alstine, J. Captan: Summary of Hazard and Science Policy Council ( HASPOC ) Meeting of January 17, 2013 : Recommendations on the Need for Acute and Subchronic Neurotoxicity Studies and an Immunotoxicity Study. March 20 , 2 013.

TXR No. 0056559

.

2013. Recore, S. Captan: Review of Human Incidents. 2/20/13. D409190.Captan/081301 Scoping Document

Page 22 of 33 APPENDIX Table 1. Summary of Doses and Endpoints Selected for Captan Risk Assessments

*This is not a dermal absorption factor but a dermal absorption rate and should be re

- evaluated in registration review. Exposure
Scenario Dose

(mg/kg/day) Endpoint Study

Acut e Dietary

Female 13+ NOAEL=10

U F = 100 FQP A = 1 30 mg/kg/day based on increased

skeletal defects (27 pre

- sacral

vertebrae ) i n fetuses

. Applie s to
females 13+ only; no appropriate endpoint for general population. Developmental

Toxicit y Stud y in

Rabbits

Acute RfD=aPAD = 0.1 mg/kg/day

Chronic Dietary NOAEL=12.5

U F = 100 FQP A = 1 2 5 mg/kg/da y base d o n decrease d pup

bod y weight One

- an d three

generatio n repro Studies

- Rat

Chronic RfD = cPAD = 0.13 mg/kg/day

Correctio n fo r ora l t o derma l exposur e necessar y (0.4 % pe r hour ; derma l absorptio n factor)*

Short

- and

Intermediate

- Term (Dermal) Oral

NOAEL=10

U F = 100 30 mg/kg/day based on increased

skeletal defects (27 pre

- sacral vertebrae) Developmental

Toxicit y Stud y in

Rabbits

Long

- Term (Dermal) None Use pattern and exposure indicate no need for long

- term risk assessment

Us e 100 % lun g absorptio n relativ e t o ora l absorption

Al l Durations (Inhalation) Oral

NOAEL=10

U F = 100 30 mg/kg/day based on increased

skeletal defects (27 pre

- sacral vertebrae) Developmental

Toxicit y Stud y in

Rabbits

*

- 3 Based on findings of intestinal tumors
i n mice Mouse OncogenicityCaptan/081301 Scoping Document

Page 23 of 33 a. Acute Toxicity

Acute toxicity values and categories for captan are summarized in the following table

.

Table 2. Overvie w o f Acut e Toxicity

Guideline Test MRID Results Category

870.1100 Acute Oral Toxicity

-

R at 00054789** LD 5 0 = 9 g/kg (M) IV

870.1200 Acute Dermal Toxicity

-

rat 40021401** LD 5 0 > 2 g/kg III

870.1300

Acute Inhalation

Toxicity

- rat 00148070** LC 5 0 = 0.72 mg/L (M)

LC 5 0 = 0.87 mg/L (F) III

870.2400 * Primary Eye Irritation

-

rabbit 00128621 Irreversibl e cornea l opacity

a t 2 1 day s i n unwashe d eyes I

870.2500 * Primary Derma l

Irritatio n

- rabbit 40021401 No t a n irritan t a t 3 days IV

870.2600 * Derma l Sensitizatio n

- guine a pig 00054791 Moderate skin sensitizer N/A

* Dat a pertainin g t o acut e ey e irritation

, derma l irritation

, an d derma l sensitizatio n ar e not required to support reregistration of the active ingredient. Data are presented for information purposes.

* * The acute toxicity endpoints, listed above, are for informational purposes only. The data supporting these

e ndpoints do not meet current acceptability criteria. The acceptability status of these data may be reassessed during product reregistration.

b. Subchronic and Chronic Toxicity

The available subchronic and chronic toxicity data for captan are summarized below.

21

- Day Dermal Toxicity: In a 21

- day dermal toxicity study, New Zealand White rabbits were exposed to Captan at doses of 0, 12.5, 110 or 1000 mg/kg/day. The NOAEL for s ystemic toxicity was 110 mg/kg/day and the LOAEL for systemic toxicity was 1000 mg/kg/day, based on reduced body weight, body weight gain and food consumption. The NOAEL for dermal irritation was less than 12.5 mg/kg/day, the lowest dose tested (LDT). Th e LOAEL for dermal irritation was equal to or less than 12.5 mg/kg/day, based on acanthosis and hyperkeratosis. ThisCaptan/081301 Scoping Document

Page 24 of 33 study satisfies the guideline toxicological data requirement for a 21

- day dermal toxicity study in rabbits (MRID 40273201).

90

- Day Inhalation Rat: In a 90

- day inhalation toxicity study, Wistar rats were exposed (nose only) to Captan (88.7%) at 0, 0.13, 0.60, 5.06, or 12.98 μg/L for 13 weeks (6 hrs/day, 5 days/week). No systemic toxicity was seen at the highest dose tested. Therefo re, the NOAEL/LOAEL were greater than 12.98 μg/L, the highest dose tested (HDT). Local irritation was observed at all doses tested. The local irritation LOAEL was equal to or less than 0.13 μg/L (LDT), based on squamous hyperplasia in the larynx of fema les. This study satisfies the toxicological guideline data requirement for a 90

- day inhalation toxicity study in rats (MRID 41234402).

Oncogenicity Rat (MRIDs 00120316, 00129157, 00129163, 00129164, 00153207): Two carcinogenicity studies were performed o n rats. In the first study, a chronic/carcinogenicity feeding study, Charles River CD strain rats (70/sex/group) were fed diets containing 0, 500, 2000 or 5000 ppm Captan (0, 25, 100 or 250 mg/kg/day) for 2 years. The NOAEL for systemic effects was 25 mg /kg/day. The LOAEL of 100 mg/kg/day was based on hepatocellular hypertrophy (males); increased relative organ weight for kidneys (males and females), increased relative organ weight for heart, brain, liver and thyroid/parathyroid (males) and decreased bod y weight for males (12%) and females (19%) when compared to controls. The Cancer Peer Review document dated 12/29/86 indicated that the maximum tolerated dose (MTD) was apparently exceeded at 100 mg/kg/day based on decreased body weight. There was a sign ificant increasing trend in males for the combined adenomas and carcinomas of the kidney in male rats. The percent incidence of combined adenomas and carcinomas of the kidney was 1, 1, 4, and 6% for 0, 25, 100 and 250 mg/kg/day groups, respectively. Ther e was no increased incidence of renal cortical/tubular cell neoplasia in females

.

In the second study, a carcinogenicity feeding study, Wistar rats (50/sex/group) were fed diets containing 0, 125, 500 or 2000 ppm Captan (0, 6.25, 24 or 98 mg/kg/day) for 30 months. The NOAEL/LOAEL for systemic toxicity were equal to or greater than 2000 ppm (HDT). There was no increase in the incidence of renal cortical/tubular cell neoplasms. There was a slight but statistically significant increase in uterine sarcoma s (4/50 vs 0/48 in controls) in the high dose group [The MTD was apparently approached at the high dose (10% body weight decrease).] The above studies, when combined, satisfy the toxicological data requirement for a chronic/carcinogenicity feeding study i n rats.

Oncogenicity Mouse ( NC I Technical Report No. 15 & MRID s 00068076 & 00126845): Three carcinogenicity studies were performed on mice. In the first one B6C3F1 mice (50/sex/treated group; 10/sex/matched controls; 65/sex for pooled controls), mice wer e fed diets containing 0, 6,000 and 16,000 ppm Captan (0, 900, and 2,400 mg/kg/day) for 80 weeks followed by no treatment for 33 weeks. The NOAEL for systemic toxicity was 6000 ppm and the LOAEL for systemic toxicity was 16,000 ppm based on decreased mean body weight fromCaptan/081301 Scoping Document

Page 25 of 33 the matched controls (about 10% less in both sexes). There was no treatment related increase in mortality and the MTD was apparently approached at 16,000 ppm. Male and female mice had an
increased incidence in combined duodenal adenoma/ polyps or adenocarcinomas at the 16,000 ppm level, with the first reported tumor at 91 weeks. A positive linear trend in males (p=0.08) and the Fisher exact test in high

- dosed males gave a probability level of 0.009. There was a minimal increase in hyper plasia of the duodenal mucosa noted in the high dose males (National Cancer Institute, 1977. Bioassay of Captan for Possible Carcinogenicity. Technical Report Series No. 15).

In a second study, ICR derived CD

- 1 Charles River mice (80/sex/group) were ini tially fed diets containing 0, 2,000, 6,000 or 10,000 ppm of Captan for 4 weeks. Subsequently Captan concentrations were increased to 0, 6000, 10,000 or 16,000 ppm (900, 1,500 or 2,400 mg/kg/day for females and at 900, 1,000 or 2,400 mg/kg/day for males) for the remainder of the study. The NOAEL for systemic toxicity was not established. The LOAEL for systemic toxicity was 6000 ppm, the lowest dose tested, based on decreased body weight gain and food consumption (no quantitative information was available ). Both high dose males and females weighed 25% less than controls. In high dose males and females, the mortality was higher, suggesting that the MTD was exceeded. At week 75, the survival in males was 68% (high

- dose), 75% (mid

- dose), 79% (low

- dose) and 83% (controls). There was an increased (p<0.001) incidence of small intestinal (primarily duodenal) adenomas/polyps and carcinomas at all dose levels. The incidences of duodenal tumors for males and females, respectively, were 2.7% and 2.8% (control), 2 7% and 31% (low

- dose), 29% and 25% (mid

- dose), and 52% and 38% (high

- dose). A positive dose

- related trend for an increased incidence of duodenal tumors in both sexes (p<0.005) was also observed. Proliferative duodenal changes appeared to occur earlier in the high dose males. There was also a statistically significant increase in gastric and duodenal hyperplasia in both sexes and in jejunal hyperplasia in females. Stomach neoplasia were not reported. This study satisfies the toxicological data requireme nt for a carcinogenicity study [83

- 2 (b)] in mice (MRID 00068076).

In a third study, Charles River CD

- 1 mice (100/sex/group) were fed diets containing 0, 100, 400, 800 or 6,000 ppm Captan (0, 15, 60, 120, or 900 mg/kg/day) and the study was terminated at 22 months due to increased mortality in the high dose males. The survival in males was 15% (high

dose) and 36% (controls) at week 75 and 7% (high

- dose) and 25% (controls) at 22 months. The NOAEL for systemic toxicity was 800 ppm and the LOAEL for systemi c toxicity was 6000 ppm based on increased mortality in males and reduced weight gain throughout the study (males and females). There was a small increase in small intestinal tumors (benign and malignant) in the male (6%) and female (8%) high dose groups (controls = 0%). The results of an Agency audit of this study suggested that there was a problem with achieving and maintaining the appropriate dose levels throughout the study. (MRID 00126845).

Chronic Toxicity Non

- Rodent: In a chronic toxicity feeding study in non

- rodents, Beagle dogs were dosed with Captan at doses of 0, 12.5, 60 or 300 mg/kg/day in capsules daily for one year.Captan/081301 Scoping Document

Page 26 of 33 The NOAEL for systemic toxicity was 60 mg/kg/day and the LOAEL was 300 mg/kg/day, based

on em esis and soft/mucoid stools. This guideline study satisfies the toxicological data requirement for a chronic feeding study in non

- rodents (MRID 40893604).

c. Developmental and Reproductive Toxicity

Developmental Toxicity in Rabbits (MRID 41826901): A developmental toxicity study was conducted with New Zealand White rabbits (20 rabbits/group). Captan was administered by oral gavage at doses of 0, 3, 10, 30 or 100 mg/kg/day from gestation days 7 through 19. The maternal NOAEL was 10 mg/kg/day and the maternal LOAEL was 30 mg/kg/day, based on reduced body weight gain, decreased food consumption, and anorexia in the does. The developmental NOAEL was 10 mg/kg/day and the developmental LOAEL was 30 mg/kg/day,
based on increased incidence of skeletal defe cts (27 pre

- sacral vertebrae) (p < 0.01) in both fetuses and litters at 30 and 100 mg/kg/day. In addition, there was increased post

- implantation loss (p <0.01), reduced mean fetal weight (p < 0.05) and increased manus score (altered growth) (p < 0.01) at 100 mg/kg/day. This study satisfies the guideline data requirement for a developmental toxicity study (83

- 3) in rabbits

.

One

- and Three

- generation Reproductive Studies in Rats (MRIDs 00120315 and 00125293):

One

- Generation Reproduction Rat: Captan was administered in the diet at dose levels of 0, 6, 12.5 or 25 mg/kg/day to male and female COBS CD rats. For this study, 15 males were mated with 30 females. No compound related effects were seen. This study by itself does not satisfy
Subdivi sion F guidelines because it is only a one

- generation reproduction study (MRID 00120315).

Three

- Generation Reproduction Rat: In the three

- generation study, the dose levels tested were 0, 25, 100, 250 or 500 mg/kg/day. For this study, 15 male COBS CD ra ts were mated with 30 females. Maternal toxicity NOAEL/LOAEL were considered to be 12.5 and 25 mg/kg/day based on decreased body weight gain and food consumption. Reproductive toxicity NOAEL/LOAEL were considered to be 12.5 and 25 mg/kg/day based on decr eased pup litter weights. Pup survival was reduced at 250 mg/kg/day or higher (MRID 00125293).

These two studies, when considered together, satisfy the toxicological guideline data requirement for a reproductive toxicity study in rats. The endpoints sele cted are based on the NOAEL of 12.5 mg/kg/day with decreased mean litter weights observed at the next higher dose level of 25 mg/kg/day. The one

- and three generation studies are acceptable together and the two studies also show that pups and parents are e qually sensitive.Captan/081301 Scoping Document

Page 27 of 33 Teratogenicity Rodent: Another developmental toxicity study was conducted with Golden Syrian hamsters (30/group). Hamsters were treated by oral intubation on days 5 through 10 of gestation with 0, 50, 200 or 400 mg/kg/day of Captan. The maternal NOAEL/LOAEL were considered t o be 50 and 200 mg/kg/day based upon reduced body weight gain and increased mortality. The developmental NOAEL/LOAEL were considered to be 200 and 400 mg/kg/day based upon increased incidences of delayed ossification, decreased weight and increased resorp tions. This study satisfies the guideline data requirement for a developmental toxicity study (83

- 3) in a second species (MRID 00086803).

d. Mutagenicity

Acceptable studies for mutagenicity fulfill all three categories for mutagenicity testing (under pre

1991 guidelines). Captan is not mutagenic in bacteria, eukaryotic microorganisms, and mammalian cells in culture. However, it was mutagenic in human fetal fibroblasts and Chinese hamster cells. Furthermore, based on the results of an in vitro calf t hymus DNA binding study, a possible genotoxic component cannot be ruled out (Ad Hoc Meeting, 9/14/98).

The following is a summary of the mutagenic potential of Captan:

Gene mutation: Captan (50% technical) was not mutagenic in vivo in host

- mediated assa ys in mice or rats with the target bacterial cultures of S. typhimurium hisG46 or TA1950, respectively. In these assays, mice were treated with Captan orally at 1 g/kg or subcutaneously at 0.5 g/kg and rats were treated with Captan orally at 2 g/kg follow ing intraperitoneal injection of bacterial cultures (MRID 00131715).

Captan at 0, 1, 5, 10, 15 or 25 μg/plate induced point mutations in E. coli and S. typhimurium strains TA100, TA1535, TA1537 and TA1538 in the absence and presence of metabolic
activatio n (MRID 00114210).

DNA Damage/Repair: Captan was negative in an assay for unscheduled DNA synthesis (UDS) in human fibroblast cells at concentrations up to severely cytotoxic levels, 50 - 6 M (or molar solution) in the absence of metabolic activation; 1000 x 10

- 6 M in the presence of metabolic activation)(MRIDs 00058608 and 00098897).

Structural Chromosome Aberrations:

- Captan was not mutagenic for inducing structural chromosome aberrations in human fetal fibroblasts exposed to Captan at 3 or 4 μg/mL dosage levels. Also, Captan was not positive for inducing chromosomal aberrations in bone

- marrow cells of the male rats treated orally up to 2 g/kg Captan in a single dose, or five doses of up to 0.8 g/kg (MRID 00131725).

Captan was positive for inducing structural chromosome aberrations in Chinese hamster cells at
4.5 x 1 0 - 5 M and above (MRID 00131727).Captan/081301 Scoping Document

Page 28 of 33 e. Metabolism and Dermal Absorption

General Metabolism: The absorption, distribution, metabolism, and excretion of Captan were studied in groups of rats administered a single oral gavage of 10 or 500 mg/kg 14 C

- Captan (labeled at 2

- C and 7

- C positions) or repeated ora l dosing of 10 mg/kg unlabeled Captan followed by a single dose of 10 mg/kg 14 C

- Captan on day 15. Captan was rapidly absorbed,
metabolized and eliminated in rats for all dosing regimens. There were no remarkable sex

- , dose

or treatment

- related difference s in the absorption, distribution and elimination of Captan in rats. The urine was the main route of elimination regardless of dosing regimen. Total recovery of radioactivity in the urine and feces was 69.3

- 90.8% and 7.3

- 25.0% of the administered dose,

re spectively in the various groups. The tissues, expired air and cage washes contained less than 0.8% for all dose groups. The identities of urinary and fecal metabolites of Captan are described in detail below. This study satisfies the toxicological guid eline data requirement for a metabolism study in rats (MRID 41505401 through 41505404).

T he initial step in the metabolism of Captan appears to be hydrolysis of Captan into two different parts, via cleavage of the N

- S bond, to form THPI (tetrahydrophthalim ide) and a derivative of the trichloromethylthio side chain. A major site of the hydrolytic cleavage of Captan is the gastrointestinal tract, although the process also occurs in blood. For each of the two different metabolites formed by the hydrolysis of Captan, analysis of 0

- 48 hour rat urine has indicated the presence of a separate metabolic pathway.

For the pathway involving the trichloromethylthio side chain group, a total of 4 urinary metabolites were found. The metabolites identified were thiophos gene, thiazolidine

- 2

- thione

- 4

- carboxylic acid, and dithiobis (methanesulfonic acid) and its disulfide monoxide derivative

. For the THPI pathway, a total of 7 urinary metabolites were found (MRID Nos. 415054

- 01 to
415054

- 04). The primary metabolite was TH PI which was formed from the cleavage of the
trichloro

- methylthio moiety. THPI represented 5.7 to 15.4% of the urinary radioactivity. Six
other metabolites identified were 3

- OH THPI, 5

- OH THPI, THPI

- epoxide, THPI

- diol, cyclohexene acid amide, and 3

- OH

- cy clohexene acid amide. Five metabolites and one unidentified compound were found in the feces. The unidentified compound is suggested to be the parent compound; however data were inadequate to show that it was unmetabolized Captan. The primary metabolite was THPI which represented 30 to 39% of the fecal radioactivity.

Although much of the toxicity of captan is attributed to thiophosgene, this moiety is not likely to
be found in tissues due to its short half

- life, and therefore, captan is regulated as t he parent compound itself.

Dermal Absorption : In a dermal absorption study, male Sprague

- Dawley rats were exposed to 2 doses (0.5 or 5 mg/animal) of ring 14 C

- labeled Captan. At 1, 2, 4 and 8 hours after dosing, 4
animals from each dose were sacrificed. The skin at the application site, blood sample, total urine and feces and residual carcass were collected and analyzed for radioactivity. A maximum daily dermal absorption rate of Captan was approximately 10% based upon 1.3%/hour for 8Captan/081301 Scoping Document

Page 29 of 33 hours at 5 mg/anim al. At 0.5 mg/animal, Captan was absorbed at 0.9%/hour. This study satisfies the guideline requirement 85

- 2 for a dermal penetration study (MRID 00117083).Captan/081301 Scoping Document

Page 30 of 33 C hemical Structure

The chemical structures of captan and its major metabolite, THPI, are presented in Table 5
below.

Table 5. Test Compound Chemical Identity and Structure

Compound

Common name captan

IUPAC name N

- (trichloromethylthio)cyclohex

- 4

- ene

- 1,2

- dicarboximide

CAS name 3a,4,7,7a

- tetrahydro

- 2

- [(trichloromethyl)thio]

- 1 H

- isoindole

- 1,3(2 H

)

- dione

CAS registry

number 133

- 06

- 2

Metabolite

1,2,3,6

- Tetrahydrophthalimide (THPI)

Metabolite

captan epoxide

Metabolite

THPI epoxideCaptan/081301 Scoping Document

Page 31 of 33 Metabolite

3

- hydroxy

- 1,2,6

- trihydrophthalimide (3

- OH

- THPI)

Metabolite

5

- hydroxy

- 1,2,6

- trihydrophthalimide (5

- OH

- THPI)

Metabolite bis(trichloromethyl) disulfide

Captan’s physicochemical properties are summarized in Table 6 below.

Table 6. Physicochemical Properties of the Technical Grade Test Compound.

Parameter Value Reference

Melting range 161

- 172 °C

Product Chemistry Registration Standard, J. Garbus, 2

- Apr

- 1987

RED; D258267, T. Morton. 3

- Aug

- 1999 pH 4.85

Density 0.55 g/cm 3

Water solubility (25 °C) <0.5 ppm

Solvent solubility (25 °C) acetone

- <5 g/l xylene

- <5 g/l

ethanol

- <5 g/l

kerosene

- <5g/l

Vapor pressure (25 °C) <10
- 6 mm Hg

Dissociation constant, pK

a not available

Octanol/water partition coefficient (K OW ) 610 ± 90

UV/visible absorption spectrum not availableCaptan/081301 Scoping Document

Page 32 of 33 International Residue Limits Captan (081301; 11/29/12)
Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 Codex 2

40 CFR 180.103: Plant: Captan (N

- trichloromethylthio

4

- cyclohexene

- 1,2

- dicarboximide) 3a,4,7,7a

- tetrahydro

- N

- (trichloromethane

sulphenyl)

- phthalimide Captan

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

US Canada Mexico 1 Codex 2

Almond 0.25 0.3 Almond, hulls 75.0

Animal feed, nongrass, group
18 0.05

Apple 25.0 5.0 15 pome fruits Po Apricot 10.0 5.0 Blueberry 20.0 5.0 20 Caneberry, subgroup 13A 25.0 5.0 raspberries 20 raspberries, Red,
Black Cherry, sweet 50.0 5.0 cherries 25 cherries Cherry, tart 50.0 Cotton, undelinted seed 0.05 Dill, seed 0.05 Flax, seed 0.05 Grape 25.0 5.0 25 50 dried grapes (=currants, raisins and sultanas) Grain, cereal, forage, fodder and straw, group 16 0.05

Grain, cereal, group 15 0.05 Grass, forage 0.05 Grass, hay 0.05

Nectarine 25.0 5.0 3

Okra 0.05

Peach 15.0 5.0 20

Peanut 0.05 Peanut, hay 0.05

Pear 25.0 5.0 15 pome fruits Po Plum, prune, fresh 10.0 5.0 plums 10 plums (including prunes) Rapeseed, forage 0.05 Rapeseed, seed 0.05 Safflower, seed 0.05 Sesame, seed 0.05 Strawberry 20.0 5 15 Sunflower, seed 0.05 Vegetable, brassica leafy, group 5 0.05

Vegetable, bulb, group 3 0.05Captan/081301 Scoping Document

Page 33 of 33 Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 Codex 2
Vegetable, cucurbit, group 9 0.05 3 cucumber 10 melons, except
watermelon Vegetable, foliage of legume, group 7 0.05

Vegetable, fruiting, group 8 0.05 5.0 tomatoes 5 tomato Vegetable, leafy, except brassica, group 4 0.05

Vegetable, leaves of root and tuber, group 2 0.05

Vegetable, legume, group 6 0.05 Vegetable, root and tuber, group 1 0.05 0.05 potato

MRLS with No US Equivalent

Cranberries 5.0

US [40 CFR §180.103(a)(2)] Canada Mexico 1 Codex 2
Livestock: Captan (N

trichloromethylthio

- 4

- cyclohexene

- 1,2

- dicarboximide) and its metabolite 1,2,3,6

- tetrahydrophthalimide (THPI),
measured as THPI N/A N/A

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

US Canada Mexico 1 Codex 2

Cattle, fat 0.15 Cattle, meat 0.20 Cattle, meat byproducts 0.30 Goat, fat 0.15 Goat, meat 0.20 Goat, meat byproducts 0.30 Hog, fat 0.15 Hog, meat 0.20 Hog, meat byproducts 0.30 Horse, fat 0.15
Horse, meat 0.20 Horse, meat byproducts 0.30

Milk 0.10 Sheep, fat 0.15 Sheep, meat 0.20 Sheep, meat byproducts 0.30

Completed: : M. Negussie; 12/03/2012

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

2 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the sample. MRLs indicated as proposed have not been f inalized by the CCPR and the CAC.