United States
Environmental Protection
Agency
Office of
Pesticides and Toxic Substances
Washington. DC 20460
June 1985
Pesticides
Captan
Special Review  Position
Document 2/3

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       CAPTAN POSITION DOCUMENT 2/3
       Office of Pesticide Programs
Office of Pesticides and Toxic Substances
   U.S. Environmental Protection Agency
            401 M Street, S.W.
          Washington, D.C. 20460

                June 1985

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         ACKNOWLEDGEMENTS
           Project Team
James Adams
John Bascietto
Lynn Bradley
Stanley Cook
Harry Day
Henry Jacoby
Bruce Kapner
Herbert Lacayo
Carol Langley
Bertram Litt
Neil Pelletier
John Quest
Esther Saito
William Schneider
Maureen Smith
Ingrid Sunzenauer
Robert Torla
Edward Zager
Senior Chemist
Wildlife Biologist
Chemist
Review Manager
Chemist
Product Manager
Review Manager
Statistician
Review Manager
Statistician
Plant Pathologist
Toxicologist
Chemist
Toxicologist
Attorney
Review Manager
Economist
Chemist

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                      Executive Summary

     On August 18, 1980, the Environmental Protection Agency
(the Agency)  issued a Notice of Rebuttable Presumption Against
Registration  (RPAR) and Continued Registration of Pesticide
Products Containing Captan  (45 FR 54938).  That action was
based on the  Agency finding that registrations of pesticide
products containing captan met the 40 CFR 162.11(a)(3) risk
criteria relating to oncogenicity and mutagenicity.  The
Agency at the same time solicited evidence on possible adverse
effects of captan regarding fetotoxicity, teratogenicity,
hypersensitivity, and acute toxicity to aquatic wildlife.

     In the United States, usage of captan is estimated at 9
to 10 million pounds active ingredient per year.  According
to Agency records, there are approximately 600 EPA registered
pesticide products containing captan as an active ingredient.
It is applied widely to control fungi on a variety of fruits,
vegetables, and ornamental crops; on plant seeds; on food
crop packing  boxes; in soil before planting; on interior
surfaces; in  oil-based paints, lacquers, paper, wallpaper
paste, plasticizers, polyethylene, vinyl, rubber stabilizers
and textiles; and in combination with insecticides on food
crops, seed treatments, and household pets.  The entire United
States population may be exposed to captan residues from
these agricultural and non-agricultural uses.  Besides these
pesticidal uses, there are products registered with the Food
and Drug Administration (FDA) containing captan, such as
cosmetics and Pharmaceuticals.

     As part  of the Special Review process, the Agency evaluates
the risks and benefits associated with the uses of a pesticide
and then proposes any regulatory actions necessary to ensure
that use of the pesticide does not result in unreasonable
adverse effects.  Regarding risks, studies conducted on mice
and rats have shown statistically significant increases in
the incidence of gastrointestinal tumors in mice and kidney
tumors in rats.  Based on the oncogenic potency demonstrated
in these studies and on estimates of human exposure to captan,
the Agency assessed lifetime cancer risks from dietary and
applicator exposure to captan and exposure to end products
containing captan as a preservative.  Although captan met the
RPAR risk criteria for mutagenicity because it induced gene
mutations in  some nonmammalian organisms, it has not caused
heritable mutagenic effects in mammalian tests.  Although
captan may cause somatic mutational events, the risk of
heritable mutagenicity to humans is low or non-existent and
does not warrant further testing at this time.

     EPA1s risk assessment for reproductive effects indicates
that the dietary exposure of the average human is greater than
the level calculated to be an acceptable daily intake; however,
EPA's final analysis of this risk will depend on the residue
data being required of registrants.

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     Existing data also indicate that captan induced terato-
genic effects, such as reduction in fetal weight and fused
ribs in hamsters.  However, additional data are needed before
a definitive judgment can be made.  Therefore, EPA is requiring
an additional teratology study in hamsters.

     Though captan is acutely toxic to fish, there are no
aquatic uses for it and leaching is not likely to occur.  It
is also unlikely to contaminate ground water.

     The benefits of captan were assessed in terms of economic
impacts which would result if the chemical were withdrawn and
users forced to substitute alternatives.  For food uses which
the Agency is proposing to cancel, moderate impacts would be
anticipated in production of apples ($0.9 - $3.3 million),
almonds ($1.4 million), strawberries  ($5.9 million), peaches
($2.3 - $5.0 million), bushbeans ($3.5 to $4.0 million),
apricots ($0.4 - $0.7 million), nectarines ($0.7 million),
and in the treatment of seeds (up to  $9.2 million).  While not
quantified, cancellation of home garden uses could result in
some increase in disease control costs.  For other food uses
of captan, the effects would be minor to insignificant.
Although the Agency is not proposing  to cancel non-food uses
of captan, as discussed below, the benefits were assessed assuming
that these uses would be withdrawn from the marketplace.  For
example, there would be moderate economic effects on the
ornamental plant industry because of  the loss of captan
availability for use on carnations and the lack of alternatives
($6 to $12 million).  For almost all  uses of captan, registered
alternatives exist; but these alternatives are usually more
expensive.  The toxicity data-base for many of these chemicals
is incomplete; some chemicals may be more, less, or equally
as toxic as captan.  Therefore a comparison of their toxicity
with that of captan is not possible at present.

     In weighing risks and benefits,  the Agency reviewed a
number of options to reduce risks.  For dietary exposure,
these included extending preharvest intervals, modifying
application practices, reassessing tolerances for captan
residues, and prohibiting post-harvest application.  However,
the available information was insufficient to assess the effect-
iveness of these measures to reduce risks and consequently
additional data are being requested under FIFRA 3(c)(2)(B).
For persons applying captan to crops, mixing or loading
formulations, working in fields treated with the pesticide,
and using end products containing the chemical, the Agency
considered requiring use of protective clothing and dust
masks or respirators.  Such action would reduce exposure by
80 to 90%, depending upon the protective measures utilized.
                              11

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     Based on its analysis of the risks and benefits, the
Agency proposes the following regulatory actions.  For
agricultural applications of captan, these are:

    — to cancel use on all food crops, but to require
       submission of residue data to determine actual
       residue levels before setting forth a final
       determination in Position Document 4.  However,
       in the final decision, the Agency will retain
       any use where data are submitted that demonstrate
       that actual residues are sufficiently lower than
       current tolerances or that modifications to application
       practices will sufficiently reduce dietary risk.

    — to continue to permit use for seed treatment,
       but to require submission of residue data to
       establish seed treatment tolerances and to
       determine whether the residues, if detectable,
       are of concern;

    — to continue to allow the feeding of detreated
       corn seed to cattle and hogs if done at least
       fourteen days prior to slaughter and if the
       corn seed residues are less than 100 ppm;

    — to require workers to wear dust masks and
       impermeable gloves when applying, mixing
       or loading captan formulations; and

    — to require harvesters and weedpickers to
       wear water-resistant gloves when working
       in fields or nurseries in which ornamentals
       have been treated with captan formulations.

     For non-agricultural use of captan, the Agency
proposes:

    — that persons incorporating captan into end
       products such as adhesives, plastics, paints,
       and cosmetics wear impermeable gloves,
       respirators (dust masks for cosmetic incorp-
       oration), and protective clothing;

    — that labels be amended to require that
       impermeable gloves be worn when applying
       oil-based paints for home or professional
       use; and

    -- that labels be amended to require people
       to wear gloves when washing their pets with
       animal shampoos containing captan.
                             111

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     The decision to cancel all food uses of captan is based
on the conclusion that the cancer risks outweigh the moderate
to low benefits.  In the absence of acceptable residue data,
the Agency based the calculations of dietary risk on established
tolerances which represent the highest residues which may
legally be present on food crops treated with captan.  While
the U.S. population may not be exposed to levels as high as
this, the Agency had no other valid data on which to base the
proposed regulatory action.  However, the Agency has required
residue data from registrants to be submitted and invites other
interested parties to submit relevant data.  The Agency
believes that the residue data will make possible further
refinement of its dietary risk assessment.

     The Agency wants to emphasize that  it  is also  concerned
about the alternative fungicides to captan.  Data available
indicate that fungicides, as a class, present toxicological
problems.  The Agency is also concerned  that the proposed
regulatory decision regarding food uses  of  captan may
encourage users to switch to alternative chemicals  which may
also have toxicological problems.  The Agency is currently
examining or will examine each alternative  fungicide  in turn
either through the Special Review or Registration Standard
processes.  The Agency encourages registrants to generate
data on safer and less toxic chemicals and  to develop alternative
methods to control fungal infestations on crops.
                              IV

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                      TABLE OF CONTENTS

I.    INTRODUCTION

     A.  LEGAL BACKGROUND	1-1

         1,  Regulatory History	1-1
         2.  Organization of this Position Document	1-2
         3.  The Special Review Process	1-2

     B.  CHEMICAL BACKGROUND	1-3

         1.  Chemical and Physical Characteristics	1-3
         2.  Registered Uses and Production	1-4
         3 .  Tolerances	1-4

II.  ANALYSIS OF REBUTTALS AND ASSESSMENT OF RISK

     A.  REBUTTAL ANALYSIS	II-l

         1.  Risks 	II-l

             a.  Oncogenicity	II-l
             b.  Mutagenicity	II-7
             c.  Teratogenicity/f etotoxicity	11-16
             d.  Metabolism	11-17
             e.  Ecological Effects	11-19

         2.  Exposure	11-19

         3 .  Benefits	11-20

     B .  ADDITIONAL INFORMATION ON RISKS	11-21

         1.  Oncogenicity	11-21
         2.  Reproductive Effects	11-21
         3.  Teratogenic/f etotoxic	11-21
         4.  Metabolism	11-24
         5.  Ecological Effects	11-34

     C.  RISK ASSESSMENT	11-37

         1.  Hazard Identification	11-37

             a.  Structure-Activity Relationships	11-37
             b.  Metabolic and Pharmacokinetic Properties....11-38
             c.  Non-Oncogenic Toxicological Effects	11-38
             d.  Short-Term Tests-Mutagenicity	11-38
             e.  Long-Term Animal Studies-Oncogenicity	11-44

                 1)  Summary of Pertinent Sudies in Animals..11-44

             f.  Human Studies	11-55
             g.  Weight-of-the-Evidence	11-55

         2.  Dose Response Assessment	11-56

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     3.  Exposure Analysis	11-58

             a.  Agricultural Uses	11-58

                 1)  Applicators and Mixer Loaders	11-58
                 2)  Harvesters (Fieldworkers )	11-72
                 3)  Cut Flower Production	11-74
                 4)  Dietary Exposure-Oncogenic Risk.	11-75
                 5)  Dietary Exposure-Teratogenic Risk	11-78

             b.  Non-Agricultural Uses	11-78

                 1)  Plastics	11-82
                 2)  Adhesives	11-84
                 3)  Paints	11-85
                 4)  Cosmetics	11-86
                 5)  Other Uses	11-87
                 6)  Summary	11-88

         4.  Risk Characterization	11-90
             a.  Dietary Risk (Food Residues)	11-90
             b.  Applicator and Mixer/Loader Risk	11-93
             c.  Risk to Fieldworkers	11-98
             d.  Risk to Workers in Cut Flower Production.... 11-100
             e.  Non-Agricultural Uses	11-100
             f.  Uncertainties  in the Risk Assessment	11-102

     D.  TERATOGENIC RISK ASSESSMENT	11-103

     E.  REPRODUCTIVE RISK ASSESSMENT	11-106

III. BENEFITS ANALYSIS

     A.  INTRODUCTION	III-l

     B.  FRUITS AND VEGETABLES	111-3

         1.  Apples	111-3
         2.  Almonds	III-4
         3.  Bushberries	111-4
         4 .  Pineapples	III-5
         5.  Strawberries	III-5
         6.  Apricots, Nectarines, and Peaches	III-6
         7.  Other Fruits and Vegetables	III-6
                              VI

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     C.  SEED TREATMENTS	III-7

         1.  Corn	 .111-7
         2.  Cotton	111-8
         3 .  Sorghum	111-8
         4 .  Soybeans	 .111-9
         5.  Peanuts	III-9
         6 .  Rice	III-9
         7.  Small Grains	111-10
         8 .  Potatoes	111-10
         9.  Vegetables	111-10
     D.  OTHER SITES	III-ll

         1.  Home Gardens	III-ll
         2.  Forest Nurseries	III-ll
         3 .  Turf	III-ll
         4 .  Ornamentals	III-ll

     E.  NON-AGRICULTURAL USES	111-12

IV.  REGULATORY OPTIONS AND RISK BENEFIT ANALYSIS

     A.  INTRODUCTION	IV-1

     B.  RISK CONCLUSIONS	IV-1

         1.  Oncogenici ty	IV-1
         2 .  Mutagenicity	IV-2
         3 .  Reproduction	IV-2
         4 .  Teratology	IV-2
         5 .  Met abol i sm	IV-3
         6.  Ecological Effects	IV-3
         7.  Risks from Chemical Alternatives
             to Captan	IV-3

     C .  BENEFIT CONCLUSIONS	IV-6

     D.  DEVELOPMENT OF REGULATORY OPTIONS	IV-6

         1.  Measures to Reduce Dietary Exposure...IV-7

             a.  Preharv est Interv al	IV-7
             b.  Modify Application Procedures	IV-7
             c.  Reassess Tolerances	IV-8
             d.  Cancel Food Crops with Highest
                 Dietary Exposure	IV-8

         2.  Measures to Reduce Exposure to Applicators
             Mixer/Loaders and Fieldworkers	IV-8

             a.  Protective Clothing	IV-9
             b.  Reentry Interv al	IV-9
                             VII

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    3.  Measures to Reduce End-Use Exposure...IV-9

        a.  Modification of Concentration	IV-9
        b.  Protective Clothing	IV-9

E.  RISK/BENEFIT ANALYSIS OF REGULATORY OPTIONS.IV-10

    1.  Agricultural Uses	IV-10

        a.  Foliar and Post-Harvest Use	IV-10
        b.  Seed Treatment Use..	IV-11
        c.  Detreated Seed Use	IV-11

    2.  Non-Food Uses (Ornamentals)	IV-12

        a.  Appl icators	IV-12
        b.  Mixer/Loaders.	IV-12
        c.  Field workers	IV-12

    3.  Non-Agricultural Uses	IV-12

        a.  Applicators	IV-12
        b.  End-uses	IV-13

            1) Plastics	IV-13
            2) Adhesives	IV-13
            3) Paints	IV-13
            4) Shampoos	IV-13
            5) Other End-Use Products	IV-14

F.  SUMMARY OF PROPOSED DECISION	IV-14

    1.  Agricultural Uses	IV-14

        a.  Foliar and Post-Harvest Use	IV-14
        b.  Seed Treatment Use	IV-14
        c.  Detreated Seed Use	IV-14

    2.  Non-Food Uses (Ornamentals)	IV-15

        a.  Foliar and Post-Harvest Use	IV-15
        b.  Applicators	IV-15
        c.  Mixer/Loaders	IV-15
        d.  Field workers	„. .IV-15

    3.  Non-Agricultural Uses	IV-15

        a.  Adhes ives	IV-15
        b.  Plastics/Fabrics	IV-15
        c.  Paints	IV-16
        d.  Cosmetics (including  animal
            shampoos and dusts)	IV-16
                        Vlll

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                       LIST OF TABLES
Number                     Title                        Page

  1     Design of Captan Chronic Feeding Studies
        in B6C3F1 Mice (NCI,  1977)	11-45

  2     Design of Captan Chronic Feeding Studies
        in Rats (NCI, 1977)	11-48

  3     High-Dose Mouse Study Design (Chevron,  1981)... .11-49

  4     High-Dose Mouse Study Mortality  Rates
        (Chevron, 1981)	11-49

  5     Low-Dose Mouse Study  Mortality Rates
        (Bio/Dynamics, 1983)	11-51

  6     Diagnosis of Gastrointestinal Tract Glandular
        Tumors for Stomach, Duodenum and/or Jejunum/
        Ileum (Bio/Dynamics,  1983)	11-52

  7     Rat Study Mortality (Stauffer/Chevron,  1982)	11-53

  8     Summary of Pathology  in Captan Long-Term
        Feeding Studies - Rats	11-54

  9     Summary of Pathology  in Captan Long-Term
        Feeding Studies - Mice	11-55

 10     Non-Dietary Exposure  Estimates for Mixer/
        Loaders	11-59

 11     Non-Dietary Exposure  Estimates for
        Applicators	11-61

 12     Potential Exposure of Workers to Captan
        During Potato Seed Piece Treatment	11-69

 13     Estimation of Fieldworker Exposure to
        Captan on Strawberries	11-73

 14     Dietary "Worst Case"  Exposure Based on
        Tolerances for Captan	11-76

 15     Captan Dietary Exposure Based on Surveys	11-79

 16     Captan Dietary "Single Serving"  Exposure
        Estimate	11-80
                             IX

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Number                    Title                          page


  17        Non-Agricultural Application Exposure
            Estimates	11-89

  18        Exposure from Non-Agricultural Product Use...11-89

  19        Estimate of Upper Bound Risk (95% Confidence
            Level) for Captan Associated with Diet Based
            on Published Tolerances or Market Basket
            Surveys	11-91

  20        Mixer/Loader Risk Estimates (No Protective
            Clothing)....	11-95

  21        Applicator Exposure and Risk Estimates
            (No Protective Clothing)	11-96

  22        Fieldworker Exposure and Risk Estimates
            for Seven Strawberry Exposure Studies	11-99

  23        Exposure and Risk Estimates for Workers
            in Cut Flower Production	11-100

  24        Risks during Application for Non-Agricul-
            tural Uses	11-101

  25        Risk from Product Use (Non-Agricultural)	11-101

  26        Teratogenic Margins of Safety for Various
            Crops from Dietary Exposure to Captan	11-104

                         Chapter III

  1         Estimated Captan Usage and Benefits of Use...111-2

                         Chapter IV

  1         Summary of Effects of Captan Alternatives....IV-4

  2         Summary of Ecological Effects of Captan
            Alternatives	IV-5

                       LIST OF FIGURES

 Number                       Title                       Page

  1         Urinary Metabolites of l^C-Captan in the
            Rat	11-26

  2         Proposed Metabolism of l^C-Captan in the
            Rat	11-28

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                       I.  INTRODUCTION

     The Environmental Protection Agency  (the Agency)  is
examining captan because of the oncogenic, mutagenic,  teratogenic,
and reproductive effects as outlined in the Position Document  1
(PD 1), published in 1980 (45 FR 54938).  The Agency is
concerned about these adverse effects of  captan, as well as
the potential effects of alternative fungicides, many  of
which may also pose risks to human health or the environment.
The Agency has reviewed a number of these fungicides either
through the Special Review or Registration Standard processes
and has taken regulatory actions to reduce risks or require
supporting data on these chemicals.  The  Agency will review
the other alternatives so that the data base will be improved
and the Agency will be able to make appropriate regulatory
decisions.

     Data available at this time has led  the Agency to conclude
that the continued registration for use of captan on food
crops and certain other uses would result in unreasonable
adverse effects on the environment.  However, in the final
decision, the Agency will retain any use  where data are
submitted that demonstrate that actual residues are sufficiently
lower than current tolerances or that modifications to application
practices will sufficiently reduce dietary risk.  Due  to a
general lack of adequate data, the Agency has had to make a
number of "worst-case" risk and exposure  assumptions in the
development of the risk assessment.  The Agency has required
the registrants to develop data pursuant  to FIFRA 3(c)(2)(B)
so that the risk assessment can be refined.  In addition,
the Agency encourages other interested parties to submit any
data that they may have which could be of use to the Agency
in the refinement of its risk assessment.  All data received
by the Agency will be evaluated and incorporated before a
final decision is issued in the Position  Document 4.

     The Agency is also concerned that if captan were  cancelled
or restricted, users would switch to alternative chemicals
that might be as toxic or more toxic than captan.  The Agency
encourages registrants and users to provide information on
methods of reducing dietary and non-dietary exposure to captan.
The Agency also encourages registrants to develop data on safer
and less toxic chemicals to control fungal infestations or to
research and develop safer methods to manage fungal pests.
These methods could include non-chemical means of control,
safer application methods and practices,  and the use of
integrated pest management.

A.  BACKGROUND

     1.  Regulatory History

     The Federal Insecticide, Fungicide,  and Rodenticide Act
as amended (FIFRA) and its regulations require the Agency to

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                             1-2

review the risks and benefits of the uses of pesticides.  On
August 18, 1980, the Agency issued a notice of Rebuttable
Presumption Against Registration (RPAR) and Continued Registration
of Pesticide Products Containing Captan.  The Agency had
determined that registrations and applications for registration
of pesticide products containing captan met or exceeded the
40 CFR 162.11(a)(3) risk criteria relating to oncogenicity
and mutagenicity.  The Notice also discussed other relevant
adverse effects including teratogenic, fetotoxic, and reproductive
effects.

     The Notice invited comments from the registrants as well
as from the public.  The comment period lasted 45 days and
all rebuttal comments received were evaluated.

     2.  Organization of this Position Document

     This Position Document 2/3 (PD 2/3) addresses the risks
and benefits of the uses of captan.  This document contains
five parts.  Chapter I is this Introduction.  Chapter II
discusses primarily the potential risks of captan use.  It
includes descriptions and evaluations of the risk inform-
ation, e; )osure data, rebuttal submissions and analyses, and
the Agency's risk conclusions.  It also addresses recent
information on reproductive effects, teratogenicity, and
metabolism.  Chapter III dicusses the benefits of different
captan uses, and discusses the assumptions and limits of
these  estimates.  Chapter IV discusses the risks of the
alternative pesticides to captan, describes the possible
regulatory options to reduce the risks of captan, evaluates
the risks and benefits of these regulatory options, and
summarizes the regulatory actions which the Agency proposes
to take  concerning captan.

     3.  The Special Review Process

     Issued under FIFRA as amended (7 U.S.C 136-136y), 40 CFR
162.11 provides that a Rebuttable Presumption Against Registration
(RPAR  or Special Review) shall be conducted if the Agency
determines that a pesticide meets or exceeds any of the risk
criteria relating to acute and chronic toxic effects set
forth  in 40 CFR 162 .11(a)(3) .  In making this determination,
the Agency is guided by section 3(c)(8) of FIFRA which directs
the Agency to begin a Special Review only if it is based on a
"validated test or other significant evidence raising prudent
concerns of unreasonable adverse risk to man or the environment."
If such  a determination is made, the registrant(s) will be
notified by certified mail and afforded an opportunity to
submit evidence in rebuttal to the Agency's presumption.  Altern-
atively, any registrant may voluntarily petition the Agency
to cancel the registration of its product(s).

     Following the initiation of the Special Review, the
pesticide use or uses of concern will enter the public
discussions stage of the Special Review process.  Registrants

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                             1-3

and interested members of the public may submit written
comments, information, or request public discussions on the
Agency's proposed actions and/or other proposals for additional
or alternative actions.  Registrants may submit information
indicating that captan does not pose a risk to man or the
environment and/or that the benefits exceed the risks associated
with captan use.  Interested members of the public may submit
information concerning the risks and benefits associated with
the use of captan.

     If risk issues cannot be resolved through voluntary
actions, the Agency proceeds to evaluate the risks and
benefits of the pesticide and to propose a regulatory solution
in this PD 2/3 and may submit a proposed Notice of Intent to
Cancel to the Scientific Advisory Panel and the Secretary of
Agriculture.  After obtaining comments from the Scientific
Advisory Panel, the Secretary of Agriculture, registrants,
and the public on PD 2/3, the Agency would issue a Position
Document 4 (PD 4) supporting the Agency's final regulatory
position, which may include a Notice of Intent to Cancel
pursuant to FIFRA, section 6.  If the Agency determines that
the risks of use exceed the benefits, the Agency would
issue a notice of intent to cancel the registration of products
intended for such use.  The notice may identify for specific
uses certain changes in the composition, packaging, and/or
labeling of the product which would reduce the risks to
levels that the Agency would consider acceptable.  Cancellation
would become effective unless within 30 days of issuance of
the notice, the registrant either requests a hearing to
challenge the cancellation or submits an application to
amend his product's registration in a manner prescribed in
the notice of intent to cancel.

B.  CHEMICAL BACKGROUND

     1.  Chemical and Physical Characteristics

     Captan is the accepted comman name for N-trichloromethyl-
thio-4-cyclohexene-l,2-dicarboximide, fungicide, known by the
trade names Merpan, Orthocide, Vondcaptan, Vancide-89 and
SR-46.  It is in the pesticide classification known as dicarb-
oximides.

     Physically, captan in pure form is an odorless, white,
crystalline substance with a melting point of 178°C.  The
technical grade material is a pungent, yellow to buff,
amorphous powder with a melting point of 160°C to 170°C.  It
is moderately soluble in many organic solvents including
chloroform, benzene and dioxane but practically insoluble in
water at room temperature.  Its empirical formula is
             and its structural formula is:

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                             1-4

                         O
                         ir
                   c     c
                c' "V \
                ||     I      N-SCC13

                Cv, ^C^ /
                 ^(T  ^C
                         II
                         O

     2.   Registered Uses and Production

     The Agency records show registrations for approximately
600 federally registered pesticide products containing captan
as an active ingredient.  These registrations are held by 139
registrants.  The technical material is produced by Stauffer
Chemical Company and Chevron Chemical Company.

     Captan was first registered as a pesticide in 1951.  The
pesticide acts as a protectant against fungal pathogens,
and is used extensively as a fungicide: (1) on a wide variety
of fruit, vegetable field and ornamental crops, some of which
are grown on home and garden sites; (2) on numerous plant
seeds; (3) on food crop packing boxes; (4) as a soil preplant
treatment; (5) on surfaces inside and outside the home; (6)
in dog and cat dusts and shampoos, oil based paints, lacquers,
paper, wallpaper paste, plasticizers, polyethylene, vinyl,
rubber stabilizer and textiles; (7) in combination with
insecticides on food crops, seed treatments, and household
pets.  It is also registered with the Food and Drug Administration
for use  in cosmetics and shampoos for humans.

     The pesticide products containing captan are most widely
used as  wettable powders (50-80% active ingredient), flowable
(38% active ingredient), and dusts (7.5-15% active ingredient).
Other formulations are commercially available as granules.

     Approximately nine to ten million pounds of captan are
used in  the U.S. annually.  The six largest crop uses are:
apples (2.9 million pounds), peaches (1.1 million pounds),
almonds  (0.9 million pounds), soybean seed (0.9 million
pounds), strawberries (0.7 million pounds) and corn seed
treatment (0.7 million pounds).

     3.  Tolerances

     The Agency has established tolerance for captan residues
(40 CFR  180.103) in or on these raw agricultural commodities
for preharvest uses or for a combination of preharvest and
postharvest uses:

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                             1-5
   (1) 100 ppm - almond hulls, beet greens, cherries1/, lettuce,
spinach;

   (2) 50 ppm - apricots1/, celery, grapes1/, leeks, mangoes1/,
nectarines1/, green onions, peaches1/, plums (fresh prunes),
shallots;

   (3) 25 ppm - apples1/, avocados, beans, blackberries, blue-
berries, huckleberries, cantaloupes, crabapples, cranberries,
cucumber1/, dewberries, eggplants, garlic, grapefruit1/, honeydew
melons1/, lemons1/, limes1/, muskmelons, dry bulb onions1/,
oranges1/, pears1/, peppers, pimentos, pineapples1/, potatoes1/,
pumpkins1/, quinces, raspberries, rhubarb, strawberries, summer
squash, tangerines, tomatoes, watermelons, winter squash;

   (4) 2 ppm - almonds, beet roots, broccoli, brussels sprouts,
cabbage, carrots, cauliflower, collards, cottonseed, kale,
mustard greens, peas, rutabaga roots, soybeans, sweet corn,
turnip greens and roots;

   (5) 0.25 ppm - taro.

     Tolerances for seed and food additives are established
in 21 CFR 193.40 for washed raisins (50 ppm)  and in 21 CFR 561.65
for detreated corn seed (100 ppm)2/.
I/  Tolerances reflect both pre- and postharvest use.

2/  Captan is removed from treated corn seed by washing or
roasting so that the seed which is left over from planting
may be safely fed to hogs and cattle.

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         II.  ANALYSIS OF REBUTTALS AND ASSESSMENT OF RISK

A.  REBUTTAL ANALYSIS

    1.  Risks

     The Agency received comments relating to risks in response to
the Captan PD 1.  Those rebuttals and the Agency's responses to the
rebuttals are contained in the following sections on oncogenicity,
mutagenicity, teratogenicity/fetotoxicity, and metabolism (Schneider
and Burnam,  1984) .

      a.  Oncogenicity

          1)  Rebuttals by Chevron Chemical Co.

     Chevron submitted detailed comments on the oncogenicity of
captan, many of which are no longer relevant because new studies,
(Chevron mouse study, 1981; Stauffer/Chevron rat study, 1982; and
Bio/Dynamics mouse study, 1983) performed since the PD 1 was
published, have enabled a more meaningful risk assessment to be
performed.   Chevron's comments are summarized below.

Comment

     Chevron presented an argument concluding that there is no
evidence that captan has any oncogenic activity in rats.  This was
based upon NCI 1977 (Gulf South); Hazleton (Weir 1956 and Dardin
1957); and an interim report of the Stauffer/Chevron (1982) joint
study.  Chevron argued that the adrenal and thyroid tumors seen
in the NCI 1977 study are attributable to spontaneous causes;
that the Hazleton study is sufficient to evaluate oncogenicity
despite the  early deaths; and that the joint Chevron/Stauffer
study showed no indication of oncogenic activity during it's
in-life portion (only the interim report was available at that
time).

Response

     The Agency believes that the earlier studies were not as well
done as the  Chevron/Stauffer rat study (1982) and, now that the
final report has been evaluated, the Agency finds evidence of
oncogenic activity (statistically significant increase in
uncommon kidney tumors in males).  The earlier studies are not
used in the Agency's risk assessment presented in this PD 2/3.

Comment

     Chevron argued that the PD 1 is wrong in stating that captan
may cause liver tumors.  The argument is based upon (1) limitations
of the Innes et al. study (1969), (2) a criticism of the statistical
methodology used to support the conclusion of the Report of the
Secretary's Commission on Pesticides and their Relationship To
Environmental Health (1969), and (3) the negative findings of

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                              II-2

the NCI (1977) and Chevron sponsored mouse studies (Chevron,
1981 and Bio/Dynamics, 1983) with respect to liver tumors.

Response

     The Agency agrees with respect to liver tumors and has not
relied on the Innes study in its evaluation of the oncogenicity
of captan because the newer Chevron mouse studies show a much higher
incidence of other tumors.  The NCI 1977 (Gulf South) study showed
a higher incidence of duodenal tumors in the mouse.  The two
registrant sponsored studies (Chevron, 1981 and Bio/Dynamics, 1983)
which looked specifically for these normally rare tumors, found
them in even higher numbers.

Comment

     Chevron argued, with respect to the treatment related
increase in duodenum tumors in mice shown by the NCI (1977) and
interim report of the Chevron 1981 mouse study, that:

  (a)  Massive doses create grossly artificial conditions
       in the duodenum which are not representative of
       those which would occur under the most severe use
       conditions.

  (b)  There are no adverse systemic effects related to
       captan even at the massive doses tested.  In fact,
       liver and lung tumors are decreased in male mice
       while survival is excellent.

  (c)  Evaluation of the risk to human health using
       ultra-conservative techniques indicates that there
       is negligible risk from exposure to captan even
       when worst case exposures are assumed.

  (d)  Using the same techniques for risk estimation, a
       greater risk can actually be demonstrated for pest-
       icides which have no apparent oncogenic activity in
       toxicology studies in animals.  Two hypothetical
       examples for which no tumors were detected in a lifetime
       study were analyzed.  The upper 95 percent confidence
       limits on risk were calculated to be in the 10~4 to
       10~6 range.

Response

     The Agency feels that comment (a) is no longer relevant
to the Agency's position because the risk assessment now presented
is based upon a study done at lower doses than those discussed
in this rebuttal comment.

     Comment (b) is irrelevant to a risk assessment for duodenal
tumors.  Oncogenic compounds frequently produce tumors at one
site or a few sites only without producing tumors in the

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                              II-3

lung or liver.  Adverse systemic effects and decreased survival
are not related to or necessary for a finding of oncogenicity.

     With respect to comment  (c), the Agency does not consider
the Chevron risk assessment to be "ultra conservative" because:

       1)  Chevron used only  its own market basket survey
           data to estimate average residues.  The Agency
           computed a somewhat higher residue (11.0 ug/day vs.
           Chevron's 6.8 ug/day) using several other sources  in
           addition to Chevron's survey (see the Agency's
           exposure assessment).

       2)  Chevron used its survey to estimate maximum residues,
           but the sample size in that survey is too limited
           for such use.  The Agency used the theoretical maximum
           residue contribution to the diet (TMRC) to estimate
           maximums.

       3)  Chevron apparently did not use a surface-area
           correction in extrapolation from mice to humans.
           The surface area adjustment is more conservative
           than the unadjusted weight basis apparently
           used by Chevron.

     The Chevron risk assessment used both the one-hit and Mantel
Bryan models for low dose extrapolation.  It applied them to
both the NCI (1977) and the Chevron mouse study (1981). Although
the method of extrapolating from mice to humans is not specified
it appears to have been done on an unadjusted weight basis.

     The Agency did not use the one-hit or the Mantel Bryan
models.  The Agency used the linearized multistage model.  It
usually gives results closely similar to the one-hit model.
The Mantel-Bryan model has an arbitrary slope.  Furthermore,
when applied to the two Chevron mouse studies (low dose and
high dose) the results from the logprobit are unstable.

     Finally, the Agency has used the surface area correction
for extrapolation from mice to humans, while Chevron apparently
did not.

     Where the Agency and the Chevron risk assessments are
most comparable (using a linear extrapolation, average dietary
exposure, and the Chevron, 1981 study) Chevron's risk estimates
were approximately an order of magnitude lower than the estimate
by the Agency.  The difference is likely to be mainly due to
the difference in extrapolating from humans to animals, but
this cannot be confirmed from the information available.

     Chevron's argument that the risks are acceptable (comment (d))
is poorly based.  Captan is being regulated under FIFRA which
specifies that risks and benefits are to be balanced in reaching
a decision on any pesticide.  The examples given by Chevron of
risks are mostly non-pesticidal (not regulated by FIFRA).

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                                II-4
Furthermore, Chevron's argument does not take benefits into
account.  The statement by Chevron that the Agency's nitrosamine
policy indicates a 10~6 risk to be acceptable is false.  The
nitrosamine policy uses the risk estimate based on a worst
case assumption that untested nitrosamines are as potent as
diethylnitrosamine to set priorities for review and data require-
ments.  This policy does not indicate any blanket acceptance of
a 1CT6 risk.

     The Chevron argument regarding upper limits on risk for
compounds without positive oncogenic data is inappropriate to
the captan decision.  The Agency is aware that studies without
positive effects do not provide a guarantee of zero risk.  This
in itself should not prevent the consideration of risk from
exposure to a compound for which there are positive oncogenic
data.

     Since the risk assessment technique uses statistical upper
confidence bounds, it is possible to compute upper limits on
risk even when no tumors are observed in the long-term study.
In such cases, the upper limit on risk will depend on how close
the estimated human exposure is to the doses in the animal
study (or to the highest dose tested if there are multiple
doses).  The closer the human exposure is to the animal dose,
the higher the upper limit on the risk will be.  One of Chevron's
hypothetical examples assumed human exposures remarkably close
to the animal dose.  The example therefore produced high upper
limits on risk (in the 10~4 range).  Such high human exposure,
relative to high doses in long term studies, is not typical of
captan or most other pesticides.

            2)  Rebuttals by Stauffer Chemical Company

Comment

     Stauffer commented that the Agency should not rely on the
Innes, et. al. study (1969) results in mice to evaluate the
oncogenic risks of captan.

Response

     The Agency has not relied on the Innes, et. al. study for
the PD 2/3.  Instead, it has used the two Chevron studies in
mice (Chevron, 1981 and Bio/Dynamics, 1983) and the Stauffer/
Chevron study in rats (1982) for the quantitative risk assessment.

Comment

     Stauffer argues that the results at the very high doses
in the NCI (1977) and the Chevron (1981) mouse studies do not
provide a valid scientific basis for predicting that captan
is an oncogenic hazard in man.

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                               II-5


Response

     The Agency now has the new Bio/Dynamics study (1983) in
mice conducted at lower levels and has used it in the quan-
titative risk assessment.  Although it can always be argued
that an effect may not appear at lower levels than those
tested, the available evidence for captan indicates that the
tumor effect occurs at a wide range of dose levels.

Comment

     Stauffer argued that the rodent models may be inappropriate
for assessing human oncogenic risks of captan because human
cells are more proficient in error-free excision repair.

Response

     The Agency realizes that there are many uncertainties inher-
ent in extrapolating from rodent studies to humans.  The possible
differences in DNA repair is just one of these factors.  It is also
possible that humans could be more susceptible than rodents to a
chemical due to metabolic differences.  There is not enough
quantitative information on these effects to incorporate them
in a risk assessment model.

Comment

     Stauffer argues that the negative results in rats tested
at doses equivalent to the mice doses (NCI 1977) indicate that
larger mammals (such as humans) will be less sensitive to
captan oncogenicity than mice.

Response

     Since the Agency now has some evidence of oncogenicity in
rats (Stauffer/Chevron rat study, 1982), the basis for this
argument has disappeared.  Stauffer commented that the age-adjusted
mortality rates from malignant neoplasms appear to be stable in
the United States since 1960, therefore, no increase from
captan was seen.

     The Agency feels that since oncogens frequently produce
results in different organs for different species, this analysis
does not provide evidence against the human oncogenicity of
captan.

Comment

     Stauffer presented a risk assessment using the one-hit model.
The risks estimated for average dietary exposure were approximately
one order of magnitude lower than those estimated by the Agency.

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                                11-6

Response

     The Agency has studied the Stauffer risk assessment.  Since
the dietary exposure estimates differed only slightly, the dif-
ference must be due to some difference in extrapolation procedures,
probably from differences in the extrapolation from mice to humans.
The Agency used the surface area correction, while Stauffer
apparently did not.

Comment

     Stauffer recommended that the Agency use a Carcinogenic
Activity Indicator (CAI), based upon the tumor incidence and dose
levels in the animal studies, as a factor in assessing oncogenic
risk.

Response

     The Agency has included the information contained in the
CAI in the quantitative risk assessment.

            3) Evaluation of Oncogenicity Studies by
               Dr. Melvin Reuber

     Dr. Reuber submitted a paper, "The Carcinogenicity of
Captan, September 4, 1980."  He stated that he examined the
histological sections and reevaluated the NCI rat and mouse
studies (1977).  He also reviewed the Innes et al. oral and
subcutaneous mouse studies (1969).

Comment

     Dr. Reuber's review of the NCI mouse experiment pointed
out the existence of duodenal tumors in both male and female
mice.

Response

     The Agency has also stated its concern for these tumors.
Two mouse studies (Chevron, 1981; Bio/Dynamics, 1983), completed
since Dr. Reuber's report, were sponsored by Chevron Chemical
Company.  The studies demonstrated a higher incidence of these
rare tumors and the Agency based its risk assessment on these
two later studies.

Comment

     Dr. Reuber stated that studies by Hazleton Laboratories
in rats (1956), Industrial Bio-Test Laboratories  in rats and mice,
(IBT B9271,IBT B9267)  and the Innes, et al. (1969) subcutaneous
mouse studies were not satisfactory.  He also noted that the
Innes, et al. oral mouse study used low doses and that "mice in
this study were examined particularly for tumors of the liver,
lung,  and lymphoreticular system, and the duodenum may not have
been adequately examined."

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                              II-7

Response

     The Agency agrees.  These studies are not suitable for
risk assessment.  The IBT studies were judged invalid by a
joint US/Canadian governmental audit in 1979.

Comment

     Dr. Reuber reported that his reexamination of the histology
sections of the NCI rat study revealed many more neoplasms
at all sites  in both males and females than were originally
reported by the NCI pathologists. He included summary tables
which listed  percentages of neoplasms in various organs.

Response

     The Agency is not able to evaluate Dr. Reuber's report
since he submitted only summary tables and did not evaluate
the histology sections animal by animal as is normally re-
quired for a  histopathology report.  Without a report for
each animal the Agency is not able to refer to the original
slide to verify his conclusions.  Stauffer sponsored a reevalua-
tion of the tissues in question by William Carlton, DVM, Ph.D.
Professor, Veterinary Pathology, School of Veterinary Pathology,
Purdue University, Indiana. Dr. Carlton furnished an animal by
animal report in which he found slightly different numbers of
neoplasms than reported by the NCI pathologists (Carlton, 1981).
Dr. Carlton concluded that "More neoplasms were diagnosed by us
in the adrenal glands, mammary gland, pituitary gland and
thyroid than  reported in the NCI bioassay.  These differences in
numbers of neoplasms were due to the greater numbers of adenomas
in our evaluation which lesions were generally designated
hyperplasias  in the NCI report.  Such differences between
histopathologic evaluations of a lesion as a hyperplasia or an
adenoma are often met with and reflect variation in the criteria
used by pathologists to differentiate between hyperplasia and
adenoma.  So  long as the criteria for differentiation are
uniformly applied across the experimental groups, the results
obtained, while numerically different, generally lead to the
same biological interpretation, such as was found in this case."

     In any event, the Agency is not using this study in its
quantitative  risk assessment, rather a more recent study that
shows more conclusive oncogenicity in the rat (Stauffer/Chevron,
1982).

    b.  Mutagenicity

        1) Mutagenicity Rebuttal by Chevron Chemical Company

     Chevron  Chemical Company submitted extensive comments on the
mutagenicity of captan.  These are summarized and responded to  in
the following paragraphs.

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                                II-8
Comment

     Chevron stated that microbial and  in vitro cell tests should
not be used for risk assessment.  Microbial testing does not
reflect the actual results  in vivo since captan is rapidly
detoxified in mammalian tissue homogenates, blood, plasma, or
by other thiol sources.  Several sources were cited to support

the inadequacy of microbial and in vitro cell culture testing
for assessing mutagenic risk to humans.  All in vivo studies
except for the T.F.X. Collins dominant  lethal study are negative.
Attempts to duplicate the Collins dominant lethal study have
produced negative results.  Ample data  exist to assess the
mutagenic safety of captan.  "The lack  of mutagenicity in vivo  in
a vast array of studies, coupled with the fact that low toxicity
permits testing a relatively high dose, clearly establish the
safety of captan."

Response

     The Agency has concluded that the  risk of heritable mutagenic
events in mammals appears to be either  negligible or lower than
can be detected in order to perform a risk assessment.  However,
somatic mutational events may occur in  vivo since tumors are
induced (or possibly promoted) in both  the mouse and rat, although
we cannot be sure of the mechanism.

Comment

     Chevron stated that the evidence that captan has caused
mutagenic effects in mammalian cells in vitro is weak and no
reliance can be placed on it.

Response

     The Agency agrees that some of the studies with positive
results were not well reported, or used unusual cell lines or
protocols; however, at least one of the studies (Tezuka et al.
1980) showed unquestionably positive results for chromosome
aberrations and sister chromatid exchanges in Chinese hamster V79
cells.

Comment

     Chevron mentioned that the major metabolite, tetrahydrophthal-
imide (THPI), is not mutagenic.  They stated several times that
the animal metabolites of captan are not mutagenic.

Response

     The Agency is not aware of a battery of tests on THPI or
other animal metabolites that would support this statement.  No
references are cited.  (There is no need for testing the metabolites

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                                II-9


in screening tests since they are present in the whole animal
tests.)

Comment

     Chevron presented many reasons why the microbial tests are
"invalid" or "not meaningful."  These reasons were generally con-
cerned with the differences in metabolism, DNA repair, and cytology

Response

     The Agency does not agree that microbial evidence is "invalid"
or "not meaningful."  As Chevron pointed out, these tests are
intended as screening tests and the Agency feels that they are
valid and meaningful to establish the intrinsic mutagenicity of
a test substance, e.g., the ability of a test substance to affect
DNA.

Comment

     Chevron cited several microbial studies (Ficson et al.,
1977; Marshall et al., 1976; Simmon, 1977; Moriya et al., 1978;
and Gabridge and Legator, 1969) to support the statement that
the activity of captan is "eliminated" when systems which
simulate the metabolic processes of whole animals are included.
The metabolic systems include: rat liver S-9 microsomal mixture
(with and without activating cofactors), rat or human blood,
rat plasma, cysteine, or host mediated systems.  The one host
mediated study that  reported positive results (Buselmaier, 1972)
injected both the captan and the bacterial cells intraperitoneally
which potentially exposed the bacteria directly to the unmetab-
olized captan. The preferred method exposes the intraperitoneal
bacteria to the metabolites of the test substance administered
by a different route.

Response

     The Agency has  referenced these studies in the PD 1 and
generally agrees with the conclusions made by Chevron.  It is
not correct to say that the mutagenicity is "eliminated" by
these systems because in many cases the activity is just reduced.
A more accurate conclusion would be that the mutagenic activity
of captan is reduced by these systems (and in some cases the
assays are not able  to detect any activity after inclusion of
these systems).  The Agency agrees that the apparent discrepancy
of the positive results of the Buselmaier study may be explained
by the above reason.

Comment

     Chevron stated  that captan is not mutagenic in mammalian
cells in culture unless there was no liver metabolic system, or
the serum normally included in the medium was deleted.

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                                11-10

Response

     The Agency realizes that the DNA damage induced in V-79
cells by captan was not detected after  inclusion of rat liver
S9 metabolic mixture  (Swenberg  et al. 1976), but DNA damage was
detected in an unscheduled DNA  synthesis assay  (UDS) with and
without rat liver microsomal mixture in SV-40 transformed human
fibroblast VA 4 cells  in culture (Ahmed et al., 1977).  Although
Arlett et al. (1975)  reported that  it was necessary to delete
the serum from the culture medium in order to see mutation
induction by captan at the ouabain  locus in V-79 cells, Tezuka
et al. (1980) reported both chromosome aberrations and sister
chromatid exchanges with captan in  V-79 cells with 10% fetal
bovine serum added to  the growth medium.

Comment

     Chevron believes  that the  UDS  study by Ahmed et al. (1977)
is invalid because quantitative data were not reported for
captan and no positive or negative  control data were presented.

Response

     The Agency acknowledges that the captan was reported merely
as "+"; however, the  authors stated this indicated a significant
difference from the control at  P< 0.05, using a subprogram
t-test comparing the mean number of grains in controls and
cells treated with pesticides at 95% confidence limits.  The
paper was otherwise well reported and the Agency believes that
it is adequate for mutagenicity screening purposes since this
type of DNA repair test is not  used for risk assessment; therefore,
exact quantification  is not necessary.

Comment

     Chevron feels that the cytogenetic assay by Legator et al.
(1969) is not valid since the karyotype stability of the L-132
human embryonic lung and rat kangaroo cell lines was not stated,
toxic levels of captan were used, the scoring methods were not
described, the data were sparsely reported, the observed
preferential breaking of the X  chromosome in the rat kangaroo
cells is unique to that cell line and cannot be predictive of
effects on other cell lines, and no mammalian activation system
was used.

Response

     The Agency realizes that these cell lines  are not often used
for these purposes and that the study was not completely reported.
The effect seen in rat kangaroo cells may be unique but that
does not preclude the relevance of  the underlying mutagenic
response.  Although toxic levels may have been  used, the production
of chromosome breaks  is meaningful  regardless of the mechanism
involved.  Despite these deficiencies,  this study is useful to
supplement the other information on production of chromosome

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                               11-11

aberrations without metabolic activation.  The results reported
here are not unexpected in view of the positive findings of
Tezuka et al.  (1980) .

Comment

     Chevron stated that the ir\_ vitro cytogenetic study by Tezuka
et al. (1978)  in human fetal fTbroblasts was negative.  The PD 1
stated that the scoring methods were not described and that the
usefulness of  the study was therefore limited.  Chevron feels
that "Tezuka clearly described the scoring method used", and
that mitosis was inhibited only at the higher doses of captan,
rather than at all doses as stated in the Position Document.

Response

     The Agency agrees that Tezuka et al. referenced Cohen and
Hirschhorn in  Chemical Mutagens, Vol 2 (ed.) A. Hollaender,
Plenum, N.Y. 1971 for a description of their scoring methods;
however, Cohen and Hirschhorn stated that "Each observer must
establish and  state his own criteria for scoring."  Chevron is
correct that captan did not inhibit mitosis at all doses.  Of
four doses with 4 hour treatment time, captan inhibited mitosis
at the lowest  and at the two high doses.  Of four doses with 24
hour treatment time, captan inhibited mitosis at the three
highest doses.  The validity of this study is not particularly
significant to the overall picture since there are adequate in
vitro cytogenetic studies reporting chromosome aberrations,
especially a later study performed by Tezuka et al. (1980) in
a different cell line, which established that captan is able
to cause chromosome aberrations in mammalian cells in culture
under some conditions.

Comment

     Chevron states that captan is rapidly and completely detox-
ified in animals.  A number of metabolism studies are cited.
(These studies are reported in the metabolism section of this
document.)  They say that "as a result of this unique detoxifica-
tion, undegraded captan could not reach the gonads to induce a
heritable mutation."

Response

     The Agency agrees that the metabolism experiments (as reported
in the metabolism section) indicate that it is unlikely that a
significant amount of captan could reach the gonads.  However,
Chevron may be overstating the situation.  The metabolism
experiments show that captan is metabolized but not necessarily
completely detoxified for the endpoint of concern (mutagenicity).
The microbial experiments, particularly Moriya et al. (1978)
in which preincubation of captan with S9 mixture, S9 fraction
without cofactors necessary for activation of the microsomal
enzymes, rat blood, or cysteine greatly reduced or eliminated
the ability of captan to induce reverse mutations in Escherichia

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                               11-12

coli WP2 her and Salmonella typhimuriumf lend support to this
theory; however, there is no quantitative study that provided
definitive proof.  It would be very difficult to devise such a
study.  It is theoretically possible that a very small amount
of captan or an active metabolite reaching the gonads could
cause a heritable mutation.  Indeed, the Stauffer/Chevron 1982
rat study showed that captan can induce kidney tumors which
indicates that an active form of captan can be found outside of

the intestinal tract.  The Agency prefers to have direct mammalian
mutagenic studies as an indication of heritable events.

Comment

     Chevron states that captan is not mutagenic in animal tests
for somatic or heritable chromosomal aberrations.  They cite the
studies as reported in the Position Document 1.  There are several
dominant lethal studies, all reported as negative except for the
studies performed by T.F.X. Collins (1972a).  Chevron finds the
following faults with this study: (1) No dose response was
observed; doubling the dose did not result in a marked increase
in the effect.  At doses where the effect is nowhere near the
maximum (i.e., only a small percentage of animals effected),
large  increases in dose should cause a significant increase in
effect, which does not happen in the Collins study.  For example,
the mean number of early fetal deaths per pregnancy reported
during week 4 of mating for rats given 100 mg/kg/day captan by
gavage is reported as 1.00 and is statistically different from
control.  However, when the dose is doubled, the index is only
1.07 and due to the large variance it is not statistically
significant. (2) The administering of captan by gavage was not
appropriate since high local concentrations of captan could
overwhelm the normal detoxification mechanism in the gastrointes-
tinal  tract.  Intragastric administration is abnormal for a com-
pound  which is ingested with the diet and degraded and "detoxified"
within the gastrointestinal tract.  The dietary route would have
been more appropriate for evaluating the mutagenic potential of
captan.  (3) The raw data is no longer available and validation
of the study is not possible.  A reproduction study by Collins
(1972b) did not reveal any dominant lethal effect as measured
by a decrease in litter size; therefore, his own data is in
conflict.  Other similar dominant lethal studies are negative
(Epstein et al., 1972; Simmon et al., 1977; and Tezuka et al.,
1978)

Response

     The Agency agrees that all other animal studies are negative.
In the Collins study (1972a), dosing by gavage is not objection-
able? a high dose is desirable for a screening study.  However,
this dominant lethal study would not be suitable for risk assess-
ment.  In addition,  the effects did not occur at a consistent
spermatogenesis stage.  The results are not found in other
similar studies.  It unfortunately is not possible to have much
confidence in the results of this study since the raw data are
not available for reevaluation and similar studies are negative.

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                               11-13

In any event, the definitive study performed for risk assessment,
the SRI 1977 heritable  translocation mouse study, was found to
be negative by an EPA sponsored Gene-Tox committee  (Generoso et
al. 1980).

Comment

     Chevron submitted  a mouse color coat spot somatic cell
assay (Litton Bionetics, 1980) which was negative.  "This test
is uniquely sensitive for an _in vivo mammalian assay since a
large number of potentially mutable loci are evaluated....The
sensitivity of the captan study was further augmented by  nearly
doubling  the group size to 105 and extending the treatment
period to the 5 day  interval, days 8 to 12 of pregnancy."

Response

     The  Agency concurs that this study was negative.  This
study is  further described in the mutagenicity risk assessment
section of this document.

Comment

     Chevron stated  that captan produced negative results in
three Drosophila assays.

Response

     The  Agency is not  able to place much reliance on negative
Drosophila tests in  risk assessment since there may be differences
in insect metabolism and intake of the test substance as compared
to mammalian systems.

           2) Mutagenicity Rebuttal by Stauffer Chemical Company

     Stauffer Chemical.  Company submitted many comments on the
mutagenicity of captan, many of which are similar to the comments
by Chevron Chemical  Company.  The following section summarizes
and responds to the  comments unique to the Stauffer submission.

Comment

     In general, Stauffer maintains that bacterial, yeast, fungal,
and mammalian cells  in  vitro systems are not relevant for predict-
ing mutagenic risk to humans.

Response

     The  Agency agrees.  The risk assessment of captan in this
document  is primarily based on iri vivo studies.

Comment

     Stauffer points out that unscheduled DNA synthesis (UDS)
assays measures only DNA repair and that the only conclusions

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                               11-14

that the Agency should draw are that the cells may have an excision
repair process for repairing captan induced modifications in
cellular DNA and that the existence of this repair process is  a
mitigating factor in determining risk.

Response

     The Agency agrees that DNA repair assays are not particularly
useful in determining risk.  They are primarily used as a rel-
atively inexpensive screening study to determine if a test
substance can affect DNA.  Heritable risk assessment testing
must involve an jln vivo test in mammals with intact DNA repair
systems measuring gonadal mutations, alkylations, or similar
process depending on the mechanism of action of the mutagen.

Comment

     Stauffer stated that the dose was very high in the V-79
cells in culture assay by Arlett et al. (1975) and that an DOS
assay in WI-38 culture human fibroblast was determined to be
negative (after a repeat experiment; the first experiment
showed that captan appeared to induce UDS after metabolic
activation) (Simmon et al. 1977).

Response

     The Agency does not use the V-79 gene mutation assay for
risk assessment, therefore the dose is irrelevant.  The assay
merely shows the potential for intrinsic mutagenic activity.  A
negative UDS assay is not incompatable with a positive gene
mutation assay and does not mitigate the necessity to perform
in vivo tests.

Comment

     Stauffer submitted a.letter from Dr. Shirasu responding to
the PD 1 comment that the scoring criteria for cells in a
chromosome analysis (Tezuka, Ando, Suzuki, Terahata, Moriya and
Shirasu, 1978) was not described.  In the letter Dr. Shirasu
states that well spread metaphases with 45 or 46 centromeres
(2n=46) were observed.

Response

     The Agency notes that the scoring criteria has not yet been
described.   This illustrates the difficulty of fully analyzing
studies published in the literature.  Detailed documentation is
needed, especially to accept a study reporting negative results.
In this case,  judging from the positive results reported for
mitomycin C and the positive results seen for captan in the
same laboratory in V-79 cells in culture (Tezuka et al. 1980)
the study is probably adequately performed.  The Agency still
is not sure what kinds of chromosome aberrations were included
in the analysis, and more important, what kinds, if any, were
excluded.

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                              11-15

Comment

     Stauffer described a study by Fry and Ficsor in which 50%
captan was administered at 250 mg/kg by i.p. injection to
Upjohn Swiss albino mice.  The numoers and handling of the mice
were not well described.  Metaphase spreads were counted for
chromosome aberrations from animals sacrificed at 6, 12, 30,
and 54 hours after treatment.  Stauffer states that captan "did
not cause any statistically significant increase in chromosome
aberrations in treated animals relative to controls."

Response

     The Agency was not able to fully analyze this study from
the abbreviated information provided in the report (published
as a "Short Communication" rather than a full paper).  The
authors themselves state that "Because of these unique chromosome
rearrangements,"  (3 metacentric chromosomes) "it cannot be
stated with certainty that 250 mg captan/kg i.p. does not break
chromosomes in vivo."

Comment

     Stauffer supports the mouse dominant lethal study performed
by Tezuka et al.  (1978) with a letter from Dr. Shirasu (one of
the authors) in which he responds to the PD 1 criticisms.  The
PD1 stated that the application of the formula given in the
paper for calculation of the percentage of dominant-lethal
mutations yielded results that differ from those reported.
Dr. Shirasu stated that this "formula was mistaken for the
following; (1 - live embryos per implants in experiment/live
embryos per implants in control) x 100.  This calculation is
appropriate for for the estimation of weak mutagen as proposed
by Rohrborn (Vogel and Rohrborn, 1970).  If captan causes
dominant lethal mutations, a significant increase in the post-
implantation losses, which is direct evidence for dominant
lethals, will be observed.  However, our results showed no such
increase even in the 600 mg/kg/day group."  The PD 1 also objected
to the protocol in that females were caged with males for 2 to
4 day intervals, depending on whether a plug was observed, the
more active males would contribute more females to the experi-
ment.  Dr. Shirasu elaborated on this point, stating that the
mating was controlled to obtain a maximum of 2 copulated female
per week (to prevent a low sperm count of males).  Stauffer
commented that the PD 1 criticism of the 6 week mating period
was unwarranted since, if Collins1 experiments are correct,
then all spermatogenic stages appear to be affected by captan
except the spermatogonial stages that would appear during the
6th week of mating.  Therefore, 6 weeks constitutes an ample
sampling period.

Response

     The Agency has concluded that the above information from
Dr.  Shirasu and the comparison by Stauffer with the Collins1

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                              11-16

study (Collins, 1972a) is adequate to allow this study to be
accepted as evidence that captan does not produce dominant
lethality under the conditions of this study at oral doses of
captan up to 600 mg/kg for 5 days.  The Agency withdraws its
objections to the use of this study.

Comment

     Stauffer cautions that quantitative risk assessments should
not be attempted from assays using microbial cells or mammalian
cells in culture due to differences in DNA repair.  Extensive
references are cited to document this.  In addition, they point
out that there are DNA repair differences between hamster and
human cells in culture as evidenced by differences to the
mutagenic action of caffeine.  They state that "The Agency
should consider the differences in DNA repair mechanisms in
extrapolating mutagenicity studies in mice to humans to estimate
mutagenic risk potential....risk estimates for humans should be
decreased when extrapolating from rodents to humans."

Response

     The Agency is not considering performing quantitative risk
assessments from assays using cells in culture.  At this time
the Agency is not quantitatively extrapolating mutagenic risk
from rodents to humans in the case of captan.  In any event,
DNA repair differences between rodents and humans would be
difficult to quantitate.

        c.  Teratogenicity and Fetotoxicity

Comment

     Stauffer Chemical Company cited studies that have been re-
viewed in the teratogenic risk section of this document and
stated that they concurred with the Agency's finding (in the
PD 1) that all currently available data on potential teratogenic
and fetotoxic effects of captan are insufficient to raise a
presumption under 40 CFR 162.11 (a)(3)(ii)(B).  They quote a
review of the literature by their consultant, William J. Scott,
D.V.M., Ph.D., Associate Professor of Research Pediatrics,
Children's Hospital Medical Center, Cincinnati, Ohio, that
"captan represents very little hazard as a human teratogen."
He recommended additional testing before any final assessment of
captan1s potential teratogenicity .

Response

     The Agency has not found significant teratogenic risk at
this time; however, an additional test has been required to
clarify some unusual findings in one of the older experiments
(Robens, 1970).

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                              11-17

         d.  Metabolism

     Stauffer Chemical Company presented a review of the metabolism
and an argument for the detoxification of captan in vivo.  The
Agency has reviewed this literature separately in this document;
however, the Stauffer rebuttal is summarized here.

Comment

    Stauffer suggested that thiophosgene is directly respon-
sible for initiating induction of tumors of the upper small
intestine in mice  in the NCI  (1977) and Chevron/Stauffer (1982)
studies.

Response

    The Agency agrees that this appears to be the case.

Comment

     Stauffer concluded that  captan is detoxified in the gastro-
intestinal tract.  "There is  strong evidence that mammals can
detoxify captan and that captan and its metabolites do not
persist in the body."  "One study" (DeBaun et al. 1974) "of
the metabolism of  captan suggests that the detoxification
process is saturable.  If it  is saturable, test animals are
disproportionately vulnerable to large doses.  There is no
evidence to show that ingestion of small amounts of captan
residue presents a risk to health."

     Stauffer pointed out that the duodenal tumors as seen in
the NCI mouse assay (1977) might be explained by "the rela-
tively alkaline nature of this region of the gut and the fact
that captan is more susceptible to hydrolytic cleavage at
alkaline pH (Daines, et al. 1957).  Hydrolysis under these
conditions and reaction with duodenal thiols may account in
part for the release of thiophosgene at this location, alkylation
of macromolecules  including DNA, and subsequent tumor formation.
The relevance and  significance of tumor induction under these
massive dosing conditions must be seriously examined and questioned
by the Agency in assessing human risk based on the NCI study."
Stauffer also stated that "Because exposure of the general
population to captan is through ingestion and because a detoxifi-
cation process exists in the gastrointestinal tract, studies
which use i.p. injections or otherwise bypass the gastrointestinal
tract are unrealistic for predicting human risks from exposure
to captan."

Response

    The Agency considers this argument to be well presented and
may have some validity; however, there are some problems with
it.  The relevant metabolic data have generally been derived
from rat studies.  No gastrointestional tumors have been found
in the rat, thus metabolism from a species that does not produce

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                              11-18

these tumors (and yet thiophosgene was formed) is being used to
explain the formation of the tumors in mice (for which no
metabolic data exists). Quantitative metabolic data in the
mouse must be presented to support this argument.  The Agency
will not require these data since a risk assessment has been
performed without considering any possible detoxification of

captan.  It also might be noted that the rat study (which had
not been completed at the time of this rebuttal by Stauffer)
has shown kidney tumors at lower levels of captan than used in
the NCI and Chevron high dose mouse experiment.

     Since Stauffer's rebuttal was presented, a low dose mouse
experiment (Bio/Dynamics, 1983) has also been completed and
submitted to the Agency.  It also shows these normally rare
intestinal tumors at a level of dose similar to that of the
Chevron high dose mouse study.  This shows that if there is an
detoxification effect on captan, it occurs at levels less than
100 ppm in the diet.  This level is much closer to actual
captan dietary residue levels.  In the mouse, 100 ppm is roughly
equivalent to 15 mg/kg of captan.  For a dietary exposure using
the theoretical maximum contribution to the diet of 7.013 mg
captan in an average 1.5 kg diet per day, a 60 kg man would
receive 0.117 mg/kg. This potential exposure is only two orders
of magnitude under the lowest tested dose.

    In the absence of quantitative data on a detoxification
mechanism for captan and considering the presence of tumors
at low levels in the mouse and rat, the Agency has concluded
that it can not justify including this inactivation theory in
its oncogenic risk assessment.

Comment

    Stauffer pointed out that mammalian DNA repair may lessen
the oncogenic risk.  "Even if an organism is unable to detoxify
by biochemical reactions all of the captan to which it has been
exposed, the organism may have other lines of defense against
tumor formation.  If captan causes tumor development by reacting
(directly or indirectly) with cellular DNA, the cell may be
able to repair the altered DNA, reversing the initial step in
tumor formation.  Thus, all relevant inutagenic test activity
should be considered by EPA in explaining the mechanism by
which captan produces intestinal tumors in mice at high doses,
and in extrapolating these findings to an assessment of human
risk. "

Response

    The Agency believes that any effect of DNA repair in
decreasing the possibility of somatic mutations which might
induce tumors would be accounted for by observing actual tumor
induction in the rodents.  In addition, any difference in
rodent and human DNA repair is theoretical and cannot be
incorporated into a risk assessment model at this time.

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                             11-19

         e.  Ecological Effects

     According to the Stauffer Chemical Company's rebuttal of
November 26, 1980 to the Agency's notice of RPAR based on
aquatic risk, they are "unaware of any aquatic use recommendations
on captan labels registered by the Agency."  Stauffer's rebuttal
of the aquatic risk criterion for captan is accepted  (Stevens,
1981).  Although captan is highly toxic to fish (not moderately
so as stated in the rebuttal) and under 40 CFR 162.11 (a)(3)(i)
(B)(3) it would appear, on the surface, that the criterion had
been met, there are several factors which the Agency must consider.

     The risk criteria under 162.11 assume direct application
to water.  Since there are no registered aquatic uses, aquatic
contamination could occur only indirectly, i.e., through drift,
runoff or leaching.  Additionally, the Agency at this time has
no reliable estimate nor measured residue data to suggest that
the magnitude of potential indirect aquatic contamination
would be great enough to result in unreasonable adverse effects
on nontarget aquatic species.  Furthermore, captan hydrolyzes
rapidly in water (half-life of 1 to 2 days, usually 1/2 day or
less; Stauffer Ref. 139 and Wolf et al., Ref 140)  and apparently
can degrade rapidly in soil under appropriate environmental
conditions, such as observed in model ecosystems.   However,
under certain field conditions captan residues may persist
longer, perhaps up to 2-3 weeks.  In specific locales, such as
seed treatments, captan residues may persist longer than observed
in model ecosystems, but these uses are not likely to result
in unreasonable adverse effects to nontarget aquatic species
because they have low rates of application.

     The Agency agrees that the available data do not provide
an adequate basis for a presumption based on aquatic risk.  Any
non-target species effects, if any, are likely to be localized
and would not be expected to be unreasonable.  However, any
significant change in use or exposure data could change the
Agency's position.

    2.  Exposure

     The Agency received comments relating to exposure in
response to the captan PD 1.  Those rebuttals and Agency
responses are contained in the following paragraphs.

     In the PD 1, a theoretical worst-case dietary exposure of
0.117 mg of captan per kg of body weight per day was calculated.
This calculation was based on existing tolerances, the extent
of crop treated (if available)  and assumed an average daily
diet'of 1.5 kg for a 60 kg person.  The Agency acknowledged
that actual levels of captan would probably be lower.

     Stauffer Chemical Company and Chevron Chemical Company
submitted data on commodities purchased from retail stores from
across the country.  They claimed that these data demonstrate
that the Agency over-estimated the dietary exposure.  The Agency

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                             11-20

considered the FDA Market Basket Survey Data, FDA Compliance/
Surveillance Survey Data, and data submitted by Stauffer and
Chevron and calculated the dietary exposure and potential  risk
using these data.  However, the Agency will not use  these  data
for regulatory purposes because: (1) the average residues  may
represent both treated and untreated samples; (2) there may be
inconsistencies  in field application practices; (3)  the handling
practices of the commodities by retailers may vary;  and (4) not all
crops were represented in these surveys.  In addition, because
tolerances represent the residues that could be legally present,
the Agency has decided to base its dietary exposure  and risk
assessment on tolerances.

     In PD 1, the Agency had very little data available in
order to assess exposure to workers.  Since the publication of
the PD 1, the Agency has received new studies and has performed
an updated exposure analysis for the PD 2/3.

     The Environmental Fate Profile for the PD 1 is  still
applicable for the PD 2/3 (Saito, 1981)

    3.  Benefits

     1,215 captan RPAR rebuttal statements were reviewed for
information on benefits, use practices, and alternative controls.
Among these, 1152 expressed endorsement of captan products and
the essentiality of various agricultural uses of captan.
Individuals expressed endorsements in terms of experience  with
captan products  (e.g., crops treated, diseases controlled, lack
of adverse health effects, and impact of cancellation) .  Many
of these endorsements (504) were submitted through form letters.
One of the form letters indicated that captan was not used,
another stated that a substitute chemical could replace captan
for a specific site.  None of the endorsements contained
information that could be useful for preparing use data reports
for economic or exposure analyses or for assessment  of
alternatives.

     Five rebuttals did not address positive benefits; two of
these requested information on risks associated with use;  one
was a brief doctor's statement which claimed to be aware of a
severe physical reaction due to captan exposure; and one called
attention to the use of captan in shampoos.  One respondent
stated that cost benefits data "is not garnered from objective
sources and is not critically assessed."

     The remaining 58 rebuttals submitted by growers, agricultural
chemical manufacturers and distributors, state extension service
personnel, grower associations, pest control applicators,  and
seed treatment contained useful information which was considered
in developing the benefits assessment in chapter III.  The
majority of these rebuttals address uses for seed treatment and
fruit,  two addressed forest tree and ornamental uses.  Rebuttals
on vegetable foliar uses were scant.

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                              11-21

B.  ADDITIONAL  INFORMATION  ON RISKS

    1.  Oncogenicity

     Since  the  PD  1 on  captan was published,  additional
information on  oncogenicity has  been  submitted  to  the  Agency.
Chevron conducted  a high-dose feeding  study  (Chevron,  1981)  and
a low-dose  feeding study  in mice (Chevron, 1983).   Stauffer
conducted a feeding study in rats (Stauffer,  1982).  An  analysis
of the data from these  three chronic  feeding  studies show  a
dose-tumor  relationship with a weight  of  evidence  classification
of B 2 (probable human  carcinogen) under  the  draft  EPA guidelines
(49 FR 46294).  This  conclusion  is based  on  adenocarcinomas  of
the digestive tract in  both sexes of  the  two  cited  mouse studies
and on kidney tumors  in male rats.  This  is further supported
by evidence from short  term studies that  show that  captan  is an
alkylator.

     A detailed description of the above  cited  studies and the
oncogenic risk  analysis is  presented  in Section  II.C.  of this
chapter.

    2.  Reproduction

    The International Research and Development  Corporation
(IRDC) conducted a 3-generation  reproduction  study  in  COBS CD rats
for the Chevron Chemical  Company (1982).  Rats were fed
captan in the diet at doses of 25, 100, 250  and  500 mg/kg/day
throughout  the  study.   For  each  generation (parental,  F^ and
F2), 15 males were mated  with 30 females.  Treatment related
effects attributable  to the administration included reduced
parenteral  (male and  female)  weight gain  at doses  of 100, 250
and 500 mg/kg,  reduced  pup  litter weights in  all litters at
all dosage  levels, and  reduced food consumption  in  all treatment
groups at all dosage  levels except for F^ males  (25 mg/kg)
and F2 females  (25 and  120  mg/kg).

     A one  generation rat study,  submitted by Chevron, was
performed by IRDC  (1982).   Captan was  administered  in  the diet
at 0, 6, 12.5,  and 25 mg/kg/day  to 15 male and  30  female COBS
rats per dose level.  No  treatment related effects  due to
captan were seen.  This study is not  adequate by itself but  is
sufficient  when used  to supplement the three  generation rat
study (IRDC #153-096, Jan.  7,  1982) to satisfy  the  reproduction
testing requirements.   When used in conjunction with the
three generation rat  study,  the  NOEL for  toxic  effects is  12.5
mg/kg/day and the  LEL is  25  mg/kg/day.

    3.  Teratology/Fetotoxicity

    Robens  et al.  (1970)  reported captan  to be  toxic and
teratogenic in  the Golden Syrian hamster.  Captan  was
administered orally to  groups varying  in  size from  2 to 10
females on  gestation days 6  to 10 at cumulation  doses  of 500,
1,000, 1,500 and 2,500  mg/kg, or single oral  doses  of  200,

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                             11-22

300, 400, 500, 600, 750 and 1,500 mg/kg on day 7 and 8.
Increased maternal mortality was observed at cumulative doses
of 1,500 mg/kg or more and at single doses of 600 mg/kg or
more.  Fetal weight was reduced after the 2,500 mg/kg cumulative
and the 1,000 mg/kg single doses.  Terata were seen at the
2,500 mg/kg cumulative dose and at single doses of 300 mg/kg
or more, and a dose-response trend was evident.  The terata
included exencephaly and fused ribs (the latter may be
attributable to maternal stress) .  Although it is difficult
to analyze the results reported in this study because of
omissions and/or inconsistencies in tabular data and because
statistical analyses were not performed, they nevertheless
are suggestive for teratogenicity.

    E. I. Goldenthal (1978) performed a study at International
Research and Development Corp. for Chevron Chemical Corp.
Captan doses of 50, 200, and 400 mg/kg/day were administered
to Golden Syrian hamsters by gavage on day 5 through 10 of
gestation.  There were 30 mated females in each of the captan
treatment and vehicle control groups.  The results suggested
that captan produced maternal deaths and weight loss at doses
of 200 and 400 mg/kg and was also fetotoxic at the 400 mg/kg
dose, resulting in decreases in the number of viable fetuses,
male to female sex ratio and fetal weight, and increases in
the number of early and late resorptions and postimplantation
losses.  In addition, rib anomalies (primarily bent ribs)
were produced by the 400 mg/kg dose level.  These anomalies
may be accounted for by a maternal stress effect upon the
fetus rather than to a teratogenic effect.

    A preliminary screening study was performed for NCI by
Bionetics Research Labs (1968).  Captan at 100 mg/kg subcu-
taneously, or orally, was administered to 21 C57BL6 female mice
on gestation days 6 to 14 and to 13 AKR female mice on
gestation days 6 to 15.  Following subcutaneous injection,
captan was associated with maternal weight loss, increased
fetal mortality, reduced fetuses per litter and reduced fetal
weights in both strains of mice.  An increased number of
abnormal fetuses, largely resulting from the occurrence of
microphthalmia, was reported in the C57BL6 strain but not in
the AKR strain of mice.  Following oral administration of
captan, maternal weight loss occurred in mice without prominent
signs of fetal toxicity or abnormalities.

    Four female New Zealand White rabbits were dosed with 80
mg/kg captan by gastric intubation on days 7-12 of gestation
and no maternal toxicity, fetotoxicity or teratogenicity was
seen (Fabro et al. 1966).  Only one dose level was tested and
the number of animals tested was very small, so the negative
results are less convincing.

    A study in New Zealand White rabbits was conducted by the
Chevron Chemical Company (1981, EPA Accession No. 246624).
Captan was administered by intragastric intubation at doses
of 6,  12,  25, and 60 mg/kg/day to groups of 15 female rabbits

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                             11-23
on days 6 through 28 of gestation.  The compound produced
maternal weight loss at doses of 12, 25, and 60 mg/kg which
was dose-related, and reduced litter weights and mean fetal
weights at the 60 mg/kg dose level.  No teratogenic effects
were observed.

    The following studies were evaluated and should not be
used for regulatory purposes due to various inadequacies:

     Two groups of 10 French Charles River Wistar rats were
treated intraperitoneally with 25 mg/kg captan (Alnot et al.
1974).  The dose level was excessively high since, of the 20
treated animals, 8 were dead 2-10 days after i.p.  injection.
Captan was found to be embryotoxic and cataracts were found
among the surviving fetuses.

    Earl et al. (1973) administered captan by capsule to
beagle dogs throughout gestation at daily doses of 15, 30, or
60 mg/kg/day.  There were 5 female dogs per group.  The most
prominent effects occurred at the 30 mg/kg dosage level and
included increases in the number of pups and litters with
terata, the number of litters with stillbirths, and percentage
of pup stillborn.  The observed terata at the 30 mg/kg dose
level included crooked tails (2 pups) and gastroschisis (1
pup).  Additional abnormalities seen at other dose levels
included single kidney (1 pup at 15 mg/kg and 1 pup at 60
mg/kg) and hydrocephalus plus open fontanel (1 pup at 60
mg/kg) .  None of the abnormalities were present in control
dogs.  Since  the effects were not dose related and showed no
consistent pattern, the results are questionable.

    A chick embryo study (Verrett et al., 1969) indicated
that captan (6 mg/kg) and its metabolite tetrahydrophthalimide
have teratogenic activity, but since the results are given as
the total number of malformations seen at all dose levels, it
is not possible to determine the magnitude of the effects at
the individual dose levels.  This study is useful as a
screening study but is not relevant for mammalian risk.

    Courtney et al. (1978) reported finding no teratogenic
effects in GDI mice at a dosage of 100 mg/kg orally and
subcutaneously, and an inhalation dosage of 483 mg/m^.
Fetotoxicity was reported in mice treated subcutaneously.
The report does not have sufficient data to evaluate.  A
monkey study was reported as negative (however, 3 abortions
among 7 monkeys at the highest dosage could be a matter of
concern).

    The IBT studies (Kennedy et al. 1968; Kennedy et al. 1975;
and Von Druska et al. 1971) have all been declared invalid
by a Canadian/U.S. audit (1979).

    The above teratology studies suggest that captan may have
the capacity  to produce fetal abnormalities in lab animals.

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                            11-24

This was indicated by findings of fused and/or bent ribs
(which may have resulted from maternal stress) and exencephaly
in hamsters following the oral route of administration, and
microphthalmia in mice following the intraperitoneal  (but not
the oral) route of administration.  Several other low level
abnormalities were seen in beagle dogs following oral admin-
istration, but no teratogenic effects were seen in studies in
rabbits.

     Because the results of the Robens et al. (1971) study with
hamsters were suggestive for teratogenicity, the Agency has
required an additional study in hamsters, dosing on only one
day rather than repeated daily dosing as usually done.  One
set of hamsters should be administered a range of doses on
day 7 of gestation, and another set should be treated on day
8 of gestation.  This study will determine the no-observable-
effect-level (NOEL).

    4.  Metabolism (Pharmacokinetics)

     Pharmacokinetic studies were performed in rats with captan
radioactively labeled either at a ring position (C^-4) or on the
trichloromethylthio side chain (C^-4 or 5^5) .  Radiolabeled captan
was administered by the oral or intraperitoneal routes in doses
ranging from 6 to 650 mg/kg.

     Captan undergoes rapid hydrolysis with scission of the N-S
bond in blood and in the gut.  At blood pH (alkaline) and in the
presence of thiols, captan is hydrolyzed to THPI (tetrahydro-
phthalimide) and to a derivative of the trichloromethylthio
group.  In the gut there is evidence of rapid reaction with
sulfite or thiosulfate radicals resulting in THPI and various
products derived from the trichloromethylthio moiety.  The gut
hydrolysis is rapid and consistent with the fact that only trace
amounts of unchanged captan are detected in rat feces after an
oral dose of 650 mg/kg (DeBaun et al. 1974).

     The metabolism of captan has been investigated almost
exclusively in rats, although one distribution study has been
conducted in mice (Selski, 1981).  Since the molecule hydrolyzes
into two different parts, the fate of the molecule has been
followed by radiolabels in two different positions.  To study the
THPI part of the molecule, 14C uniformly labeled in the carbonyl
group was used (Hoffman et al. 1973); to study the trichloro-
methylthio moiety, the 14C-label at the methyl carbon was used
(DeBaun et al. 1974).  In addition, some studies have attempted
to follow the metabolism of captan labeled with 35g in the
trichloromethylthio moiety (Seidler et al. 1971; Couch et al.
1977) .

     The fate of captan uniformly labeled in the carbonyl group
was elucidated by Hoffman et al. (1973).  After oral administration
of single oral doses of 77.4 to 91.9 mg/kg of 14C=0 captan,  no
unchanged captan was detected in the urine.  Rats excreted 92% of
the radiolabel within 48 hours and 96.8% of the radiolabel within

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                            11-25

96 hours.  Most of the 14C  (84.5%) was excreted in the urine
with only 12.3% excreted  in the feces and none detected in expired
air.  Tissue residues at  96 hours did not exceed 0.1% of the
total 14C administered.   No significant difference in elimination
rates of the 14C was detected between male and female rats.

     In vivo biotransformation of the ring structure of captan
followed four pathways after initial hydrolytic cleavage of
14C-captan to THPI and the  trichloromethylthio side chain moiety
(Figure 1).  THPI was the precursor for these four pathways
since identical urinary metabolites were found after oral
administration of THPI-14C=0.  of the '14C that was found in rat
urine 15% was present as  14C-THPI.

     The following metabolic pathways were observed (Figure 1):

          a.  Pathway (I):  the major urinary metabolite was
              the trans-3-hydroxy product, 3-OH-THPI, which
              accounted for 38.4% of the urinary 14C.  This
              was further degraded to 3-OH-THPAM (trans-1-
              carboxy-2-carboxamido-3-hydroxy-4-cyclohexene),
              which represented 7.1% of the urinary 14C.

          b.  Pathway (II):  epoxidation of THPI in positions 4
              and 5.  In  rat urine, 5.2% of the 14C-THPI that was
              found was present as !4C-THPl-epoxide (trans-1,2-
              dicarboximido-4,5-epoxy-cyclohexane).  This compound
              was subsequently hydrolyzed to yield 4,5-di-OH-THPI
              (trans-1,2-dicarboximido-4,5-dihydroxy-cyclohexane),
              which represents 10.9% of the urinary 14C.  Intra-
              peritoneal  injection of THPI-epoxide to rats resulted
              mainly in unchanged epoxide and an unidentified
              "minor" metabolite.

          c.  Pathway (III):  hydrolysis of THPI to yield 11.7%
              of THPAM (trans-l-carboxy-2-carboximido-4-cyclohexene)

          d.  Pathway (IV):  ring hydroxylation of THPI in the 5
              position and subsequent rearrangement of the double
              bond giving 5-OH-THPI (10.1%).

          e.  A minor pathway involving conversion of THPI to an
              unidentified metabolite which accounted for 1.2% of
              the urinary 14C.

     Neither glucuronide  nor sulfate conjugates were detected in
rat urine.  Reaction of the urine with B-glucuronidase and
sulfatase gave negative results.  Since the molecular weight of
the THPI derivatives were all below 325 and since no conjugation
was detected, biliary excretion was considered unlikely.  There
was no attempt to analyze fecal metabolites.  Tissue distribution
studies revealed tissue residues (expressed as ppm captan
equivalents) to range from 5.47 (in hide)  to 42.90 (in kidney) at
24 hours.  At 48 hours, the range of values was 0.0 to 2.83 ppm.

-------
                       11-26
         O
         II
           NH
S-OH-THPI
          HO
     3-OH-THPI
          HO
     3-OH-THPAM
                IV
    a
      I
    a
                         O
                         II

                         c\
                            NSCCL3

                          II   CAPTAN
                          O
O
II
C,
 NH
/     III
                7
                 \
                  NH
C'
II
O
O
II
C-NH2
C-OH
II
O
                         c
                         II   THPI
CŁ
   J
                     X
             cc:
                     O
                     II
                     C-NH2
                     C-OH

                        THPAM
                      NH
                                      THPI-EPOXIDE
                           HO

                           HO
          o
          II
          c,
                      NH
        II  4,5-diOH-THPI

        O
Figure 1.  Urinary Metabolites of **C-Captan in the Rat

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                            11-27

The values were negligible thereafter.  No fat accumulation was
noted.

     The metabolic  fate of captan labeled on the trichloromethyl-
thio moiety was monitored after oral or intraperitoneal administration
to rats (DeBaun et  al., 1974).  After a single oral dose of
14C-captan (100 mg/kg), 50% of the 14C was excreted in urine,
feces, and air within  9 hours.  In comparison, excretion of 50%
of a single intraperitoneal dose of !4C-captan did not occur
until 48 hours after dosing.  Four days after a single oral dose,
the cumulative distribution of the 14C was 51.8% in urine, 15.9%
in feces, and 22.8% in expired air.  Comparable figures for the
intraperitoneal route  after 4 days were 45.5% in urine, 5.8% in
feces, and 18.4%  in expired air; between 4 and 10 days, another
14.8% was eliminated  in urine and 18.8% in feces.

     In vivo biotransformation of the side chain moiety of orally
administered captan followed three Pathways after initial hydrolytic
cleavage of 14C-captan to the THPI ring structure and the
trichloromethylthio moiety (Figure 2).

          a.  Pathway  I:  an initial reaction involving the
              formation of thiophosgene from the trichloromethylthio
              side chain moiety.  The thiophosgene is the precursor
              for the  remaining pathways described below.
              Thiophosgene is probably formed in the more alkaline
              parts of the gut.  In vivo, thiophosgene may arise
              from reaction of Na2SO3 or thiosulfates with captan.
              This reaction also occurs in vitro.

          b.  Pathway  II:  reaction of thiophosgene with sulfite
              ion to yield dithiobis (methanesulfonic acid)
              (metabolite A) and its disulfide monoxide derivative
              (metabolite B).  The former metabolite represented
              54% and  the latter metabolite represented 13.8% of
              the urinary 14C, respectively.  These metabolites
              are the major ones formed after oral administration,
              but these are not formed after interperitoneal
              administration indicating that the reaction with
              sulfite  ion takes place in the gut or by action of
              the intestinal mucosa.

          c.  Pathway  III:  condensation of thiophosgene with
              free cysteine or free glutathione to form a
              thiazolidine derivative, thiazolidine-2-thione-
              carboxylic acid (metabolite C), which is not
              metabolized further in the rat and is excreted in
              the urine.  This metabolite represented 18.6% of
              the urinary 14C.

          d.  Pathway  IV:  hydrolysis and/or oxidation of
              thiophosgene to CC>2.

     Following oral administration of !4C-captan, metabolites
A, B and C accounted for 86% of the urinary radioactivity.  After

-------
                          11-28
Thiazolidine-2-thione-
4-carboxylic acid
Dithiobis [methane
sulfonic acid]  and
its disulfide monoxide
derivative
  Figure 2.  Proposed Metabolism of 14C-Captan in the Rat

                             .c.»c

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                            11-29

intraperitoneal administration, metabolite C was the major
urinary metabolite since neither metabolite A nor B was formed
with this route of administration.

     Tissue residue studies indicated that there was no organ-
specific accumulation after oral administration and no significant
difference between tissue residues in male and female rats.
Total 14c present in tissues 4 days after dosing was 0.6% of the
dose of !4C-captan.  At day 8, only the bladder, kidney, and lung
had a 14C-content in excess of 1 ppm.

     The differences between the rates of excretion and the
difference in metabolic pathways in the gut after oral and
intraperitoneal dosing indicate that captan is degraded in the
gastrointestinal tract and that oral and intraperitoneal doses of
captan may not be equivalently toxic.

     Pharmacokinetic studies, using 35g.-captan were conducted by
Seidler et al. 1971, in rats of unspecified strain.  Of the 35S
in the single oral dose of 35S-captan (either 143 or 390 mg/kg),
92% was excreted within the first 24 hours after dosing.  (Of
this amount,  38% was excreted in the feces and 55% in the urine.)
On day 2, 5%  of the 35S was excreted (1% in the feces, 4% in the
urine) .  A total of 101% (j^8%) of the administered dose was
recovered in  the excreta within 3 days after dosing.  As indicated
above, DeBaun et al. (1974), found only 15.9% of radiolabel in the
feces after an oral dose of 100 mg/kg !4C-captan, whereas the
result of Seidler et al., 1971, for fecal radiolabel was 38%.
This discrepancy may be due to the possible use of different
strains of rats, as well as the use of a dose almost four times
that used by  DeBaun et al. (1974).  Larger amounts of 35g-captan
may not have  been absorbed in the study of Seidler et al. (1971).
In addition,  the vehicle was not specified by Seidler et al.
(1971), and may have affected the absorption.

     On the basis of thin-layer chromatography and Rf values, a
number of metabolites in rat feces and urine was identified which
cochromatographed with known substances.  Feces of rats dosed
orally with 35g_captan contained 35g_captarlf 35s-giutathione, and
an unidentified metabolite with an Rf value of 0.76. The urine
contained 35g_captan, 35s-giutathione, tne thiazolidine derivative
of crysteine, and an unidentified metabolite with an Rf value
of 0.76.  Unmetabolized captan has not been detected in the
urine in other studies; however, DeBaun et al. (1974) did
detect unchanged captan in feces in preliminary metabolism studies
utilizing a high dose (i.e., 650 mg/kg)  of [trichloromethyl
l^c]captan.  The presence of the ^Sg-giutathione in the urine and
feces may be accounted for by isotopic exchange between oxidized
glutathione and 3^S-thiazolidine (Richmond and Somers, 1968).  In
fact, the interpretation of data based on the use of 35g as a
marker is difficult because isotope exchange occurs.

     In tissue distribution studies, trace amounts of the 3^5
label were measured in various organs on the 1st day after oral
administration.  Concentrations (expressed as % of administered

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                            11-30

dose) were:  liver (0.45%), serum (0.04%), muscle (0.28%), kidneys
(0.011%), brain (0.004%), and spleen (0.002%).  On the 3rd day
after administration, the amounts of the label increased in serum
(0.05%), muscle (0.088%), kidneys (0.023%), brain (0.01%) and
spleen (0.013%), and declined slightly in liver (0.041%).  This
finding was not apparent with a l^C-label (DeBaun et al., 1974;
Hoffman et al., 1973) with which the residues decreased after the
single dose.

     Another study utilizing 35S-captan was conducted by Couch et
al.  (1977) in male Sprague-Dawley rats.  A single dose of 6 mg/kg
was  administered intraperitoneally in 0.5 ml of corn oil to
normal, sham-operated animals and to partially hepatectomized
animals.  In addition, multiple dose experiments were performed
where three doses of 6 mg/kg were administered to sham-operated
animals and to partially hepatectomized rats at 24-hour intervals.
Excreta were collected every 24 hours, and tissue levels were
measured at sacrifice (3 days after a single dose or 24 hours
after the third multiple dose).  After the single intraperitoneal
dose, there was no difference in the percentage of label excreted
by normal, sham-operated animals and by hepatectomized animals.
After 24 hours, an average of 59.6% of radiolabel appeared in the
urine, with 7.6% appearing in the feces.  At 48 hours, the urine
contained an average of 11.1% of the radiolabel and the feces
contained an average of 3.9%.  At 72 hours, the urine contained 5.3%
and  the feces 1.2%.  The average total excretion over 72 hours
was  76.0% in urine and 14.1% in feces.  These results are consistent
with the pharmacokinetics observed after intraperitoneal
administration of 20 mg/kg 14C-captan (DeBaun et al. 1974).  The
values reported by DeBaun et al. (1974) after 96 hours were
45.5% in urine, 5.8% in feces, and 18.4% in the expired air.
Clearly, excretion of either 35S- or 14C-captan is much slower
after intraperitoneal administration.

     Levels of 35g in the tissue of sham-operated rats were
compared after single or multiple doses.  The residue levels at
72 hours in the tissues after a single intraperitoneal dose were
highest in the blood plasma (4.50 +_ 0.65 ug of 35S-captan
equivalents) and spleen (3.00 +_ 2.10); intermediate in the lung
(1.80 + 0.24), kidney (1.60 + 0.12), and bone (1.30 + 0.30);
and  lowest in the liver (0.71 +_ 0.08), heart (0.52 + 0.21), and
brain (0.21 + 0.02).  The tissue levels after multiple adminis-
tration were two or four times greater than the values obtained
with single administration.

     Captan treatment of isolated liver nuclei with 12 ug/ml
of the 35s-iabel f°r °ne hour resulted in binding to nuclear
proteins.  The degree of binding was 39% in acidic ribonucleo-
proteins, 14% in deoxyribonucleoprotein (including histones), 10%
in nuclear sap protein,  and 16% in "residual" protein fractions.
In contrast to these in vitro studies, nuclei isolated from rat
liver after animals had received multiple intraperitoneal doses
of 35S-captan contained exceedingly low levels of 35S (i.e.,
0.008 to 0.009 ug/g tissue).  The data suggest that although the
radiolabel can bind to protein components of genetic material and

-------
                            11-31

possibly exert toxic effects, it is likely that very little of
the 35s actually reaches liver nuclei following administration to
the whole animal due to metabolism, as judged by the low levels
of radioactivity that were observed.

     In a study in Swiss-derived CD-I mice, the ability of orally
administered captan to associate with DNA of several organs was
investigated (Selsky, 1981).  Mice were administered a single
oral dose of 156 mg/kg of  [l4C-trichloromethyl]captan of high
specific activity (50-56 mCi/mmole) and the amount of 14c associated
with DNA from test is, duodenum, stomach, kidney, and liver
determined 24 hours later.  Values for the association of the
radiolabel/DNA nucleotide molecule (expressed as the number of
trichloromethyl carbon atoms/DNA nucleotide) ranged from 1.4-5.1 x
10~6 for testicular DNA to 1.4-1.8 x 10~5 for stomach DNA.  The
association levels among the different tissues were similar, and
were not higher at sites of potential mutagenicity (i.e., testis)
or carcinogenicity (i.e., duodenum) than at other sites.  In
those organs the radioactivity did not appear to be covalently
bound to DNA since much of it could be lost from the DNA fraction
upon dialysis against Tris-EDTA buffer.  It should be noted that
the identity of the radioactivity labeled moiety was not determined
in this study.  Furthermore, the dialyzable radioactivity may
have been coprecipitated with the DNA and may not have actually
been bound to that material.  When preliminary experiments of a
similar nature were performed in both mice and rats to evaluate
14C-captan binding to tissue DNA by using higher doses of chemical
(300 and 1600 mg/kg)  but lower specific activities (0.19-1.9
mCi/mmole), no radioactivity was found associated with DNA (Selsky,
1981) .

     There is evidence that captan can inhibit hepatic microsomal
hydroxylase activity in vivo.  Truhaut et al. (1974) administered
captan intraperitoneally at 10 mg/kg to male Sprague-Dawley rats.
The hydroxylation of zoxazolamine was inhibited and paralysis
time was significantly prolonged (p < 0.01).

     Peeples and Dalvi (1978) showed that liver microsomes prepared
from Sprague-Dawley rats given captan orally at 650 mg/kg and
100 mg/kg had diminished aniline hydroxylase activity.  The
hydroxylase activity was decreased by 10% at 100 mg/kg, and by
approximately 50% at 650 mg/kg.  When diethyl maleate, a liver
glutathione inhibitor, was administered intraperitoneally in
combination with 650 mg/kg captan administered orally, the aniline
hydroxylase activity decreased a further 25%.  Liver microsomes
prepared from rats administered captan intraperitoneally at 20 mg/kg
decreased the aniline hydroxylase activity 20%.

     The ir\ vitro effect of captan on rat hepatic microsomal
cytochrome P-450 was studied by Dalvi and Ashley (1979).  Captan
at a concentration of 12 uM produced a 50% reduction of cytochrome
P-450.  This loss was not prevented by EDTA, which suggests that
lipid peroxidation does not occur in captan metabolism, but was

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                            11-32


prevented by the presence of reduced glutathione at a concentration
of 0.5 mM.

     Urbanek-Karlowska (1977) measured the activity of hepatic
microsomal enzymes in relation to dietary protein and 0.1% captan
fed in the diet.  All rats on a 24%, 8%, or 4% protein diet and
0.1% captan for 8 weeks showed increased activity of p-nitroanisole
demethylase.  The rats on a 24%, 8%, or 4% protein diet and 0.1%
captan for 12 weeks showed significant decreases in mean liver
microsomal protein.

     Other studies have examined the effect of captan on oxidative
phosphorylation in isolated rat liver mitochondria.  Nelson
(1971a, b) demonstrated inhibition of succinate, glutamate, and
B-hydroxy-butyrate supported active (state 3) respiration.  The
addition of cysteine partially reversed this effect.  The inhibited
enzymes all contain functional sulfhydryl groups.  Nelson (1971b)
also showed that captan affects the permeability of the mitochondrial
membrane, resulting in mitrochondrial swelling.  It is not clear
whether the membrane effects are associated with the effects of
captan on oxidative phosphorylation.

     Engst and Raab (1973) administered a single dose of captan
(route unspecified) at 5% of the LD5Q.  Blood was examined at 3
and 24 hours after dosing.  Sulfhydryl groups in erythrocytes
were reduced approximately 50% at 3 hours and 25% at 24 hours.

Summary of Metabolism Studies

     Absorption of captan appeared to occur following oral
administration as indicated by the appearance of radiolabeled
material in the blood of lab animals.  At 1 day after dosing,
blood levels ranged from 2.95-21.8 ppm captan equivalents; at 8
days after dosing levels in blood declined to 0.4-0.98 ppm.  At
the earlier time period, most body excretory organs contained
similar or greater concentrations of radioactivity than blood
(e.g., 31.2-33.8 ppm in stomach and intestine; 6.1-42.9 ppm in
kidneys and bladder; 4.2-17.7 ppm in liver; and 14.5 ppm in
lung).  After 8 days, only the kidney, bladder and lungs tended
to have concentrations of radioactivity greater than that seen in
blood.  No unusual localization of radioactivity occurred in
other body tissues.

     Captan is extensively metabolized in the rat after oral
administration.  The initial step in the process appears to be
hydrolysis of captan into two different parts, via cleavage of
the N-S bond, to form THPI (tetrahydrophthalimide) 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.  The reaction is
facilitiated in the presence of thiol compounds (e.g., glutathione
and cysteine) and is pH dependent, accelerating as the pH increases
(e.g., in moving from the stomach to the small intestine).  For
each of the two different metabolites formed by the hydrolysis of

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                             11-33

captan,  analysis  of  0-48  hour  rat  urine  has  indicated  the presence
of  a  separate metabolic pathway.   For  the THPI pathway,  the
following  four  reactions  occurred:   (1)  ring  hydroxylation of
THPI  to  3-hydroxy THPI with  further  degradation  to  3-hydroxy THPAM
(3-hydroxy-trans-l-carboxy-2-carboxamido-4-cyclohexene)  as the
major reaction;  (2)  epoxidation of THPI  to THPI-epoxide  with
further  hydrolysis to 4,5-dihydroxy-THPI; (3) hydrolysis of THPI
to  THPAM;  and  (4)  ring hydroxylation of  THPI  with subsequent
rearrangement of  the double  bond to  form 5-hydroxy-THPl.  For the
second pathway  involving  the trichloromethylthio side  chain group,
the following four reactions occurred:   (1)  conversion of the
trichloromethyl-thio moiety  to thiophosgene,  a precursor for the
remaining  reactions;  (2)  condensation  of thiophosgene  with either
free  or  peptide  bound cysteine to  form thiazolidine-2-thione-4-
carboxylic acid;  (3) reaction  of thiophosgene with  sulfite to
form  dithiobis  (methanesulfonic acid)  and its disulfide  monoxide
derivative:  this is the  major reaction  after oral  dosing but
does  not occur  after intraperitoneal injection,  indicating that
it  occurs  in the  gut; and (4)  hydrolysis and/or  oxidation of
thiophosgene to  CC>2.  An  analysis  of feces for metabolites of
captan has not  been  performed.

      The major  route of excretion  is via the  urine; additional
excretion  occurs  in  feces and  expired  CC>2 •   Over 4  days  the total
excretion  of an  orally administered  dose of  radiolabeled captan
is  approximately  80-92% (40-81% in urine, 7-40%  in  feces, and 0-23%
in  expired air).   The rate of  excretion  after oral  administration
is  rapid,  with  50% of the total excretion occurring in the first
9 hours.   After  intraperitoneal injection, approximately 70-90%
of  an administered radioactive dose  is also  excreted over 3 to 4
days  (45-76% in  urine, 6-14% in feces, and 0-18% in expired air),
but the  rate of  excretion is delayed with 50% of the total
excretion  occurring  in the first 48  hours.   Essentially  all of
the radioactivity found in the urine and feces after oral or
intraperitoneal administration represents metabolites  of captan
with  little or  no unchanged  captan present.

      Differences  in  excretion  pattern  occurred with oral and
intraperitoneal administration of  radiolabeled captan.   With
intraperitoneal administration two metabolites normally  seen
after oral dosing, namely dithiobis  (methanesulfonic acid) and
its disulfide monoxide derivative  formed by  the  reaction of
thiophosgene with  sulfite were not formed, and the  rate  of
excretion  was slower than with oral dosing.   These  differences
•suggest  that captan  is susceptible to  metabolism in the
gastrointestinal  tract after oral  administration.

      An  apparent  difference  in excretion pattern between the use
of  large and small oral doses  of captan  also  occurred.   Following
the oral administration of 650 mg/kg of  [trichloromethyl-l^c]captan,
28.7% of the administered  radioactive  dose was excreted  in the
feces, and unchanged captan  was detected in  the  feces.   In
contrast,  following  the oral administration of lower doses of the
radiolabeled captan  (12 to 134 mg/kg), only  7.2  to  11.3% of the
administered radioactive  dose  was excreted in the feces, and no

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                              11-34

unchanged captan was detectible.  The differences may reflect
excretion of non-absorbed captan when high doses of the chemical
are administered.

Conclusions

     There are differences in the metabolic fate of captan if
exposure occurs by any route other than the oral route.  The data
on intraperitoneal administration indicate both a slower elimination
and different reaction products.  For captan, the metabolic
pattern after intraperitoneal administration is probably closer
to the fate of the molecule administered dermally or by inhalation
because gut metabolism is bypassed.  Although absorption by the
dermal and inhalational routes will initially enter the systemic
circulation, captan entering by these routes will subsequently
reach the liver where it will come in contact with high glutathione
levels.  Metabolism thereafter should be the same as that occurring
after intraperitoneal administration.

     The majority of the pharmacokinetic studies of captan were
performed in rats, and only one pharmacokinetic study appears to
have been performed in mice (Selsky, 1981).  This study showed
distribution of radioactive carbon throughout body tissues,
including the tests.  This may not be of biological concern
because even though comparable levels of radioactivity were
found throughout various body organs the only tumorigenic effect
found in mice was confined to the intestine.  Thus, it is likely
that the radioactivity is not associated with a biologically
active metabolite of captan.

     THPI is present in both plants and animals as a captan
metabolite and may be of toxicological concern.  The Agency does
not have sufficient data on residues of THPI to perform a risk
assessment and will therefore be requesting such data pursuant to
FIFRA 3(c)(2)(B).

    5.  Ecological Effects

        a.  Use

     Captan is used as a fungicide on a variety of sites.  For
purposes of determining ecological effects, the major uses
for captan are assumed to be apples, strawberries, potatoes,
(seed piece treatment), soybeans (seed treatment), almonds and
home gardens.  For exposure analysis purposes these uses were
considered representative of other uses (Stevens, 1982).

        b.  Environmental Chemistry

     The half-life of captan in soil can range from one day to
more than two months, depending on soil type and moisture.
Under field conditions, two to three weeks is the expected
half-life.  Half-lives in water are reported to be approximately
12 hours between pH 2 and 6, 2.5 hours at pH 6-7, and 10 min.

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                               11-35


at pH 8 and above.  Captan effects on microbial populations
are temporary  if  at all.  Captan did not demonstrate a potential
to bioaccumulate.  Captan is not expected to leach.

     c.  Toxicity of Captan to Aquatic Organisms

     The 96-hour  LC$Q values for various fish species exposed
to captan  technical (90-100% a.i.; Johnson and Finley, 1980)
range from 49  (40.1-59.9) to 141 (119-167) ug/1.  The rainbow
trout (Salmo gairdneri) and bluegill (Lepomis macrochirus) 96
hour LC50  values  are 73.2 (66.6-80.7) and 141 (119-167) ug/1
respectively.

     The MATC  for fathead minnow is >16.5 to <39.5 ppb.  The
48-hour LC5Q for  Daphnia magna is estimated to be greater than
7.1 mg/1 (ABC,  1980).

     Caldwell  (1977) conducted a series of acute and chronic
tests on various  pesticides using the Dungeness crab (Cancer
magister).  The 96-hr LC5Q values for the zoeal, juvenile and
adult stages were each greater than 10 ppm.  In chronic tests,
the level  at which captan significantly affected (1) egg hatch
and pre-zoeal  development is >10 ppm, (2) first stage zoeal
motility 3.3 ppm, (3) continued zoeal survival 20 ppm,
(4) juvenile survival >200 ppm and (5) adult survival >200 ppm.

     Metcalf and  Sanborn (1975) reported on a model ecosystem
study designed  to simulate the fate on captan in a farm pond.  A
20 gal aquarium with a steeply sloping sand bottom was filled
with 71 water  at  26.5°C, and sorghum (Sorghum halopense) was
planted along  the bank.  After plankton (diatoms, rotifers,
etc.), Daphnia magna, mosquito larvae (Culex pipiens), algae
(Oedogonium cardiacum), and snails (Physa spp.), were added to
the water, radio-labeled captan - l^c was applied to the sorghum
seedings at 1.0 Ib Al/acre, and slat marsh caterpillars (Estigmene
acrea) were then put on the sorghum plants.  Thirty (30) days
after captan application, mosquitofish (Gambusia affinis) were
added to complete the food chains.  After a total of 33 days,
samples were taken from the water, mud and remaining flora and
fauna for  residue analysis.  No intact captan was identified in
any sample.

        d.  Summary of Relative Risk to Aquatic Organisms

     Although  captan is very highly toxic to fish (96-hour LC5o's
_< 141 ppb)  , we believe that the available data provide an adequate
Hasis for  concluding that any nontarget aquatic effects, if any,
are likely to  be localized.  There are no aquatic uses for captan
and little movement of captan through leaching or runoff is
expected.  Additionally, captan hydrolyzes very rapidly in water
(half-life up  to one to two days, usually 1/2 day and less).

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                              11-36
        e.  Toxicity of Captan to Terrestrial Wildlife

     Schafer (1972) reports the acute oral 1,050' s of captan for
red-winged blackbird ( Agelaius phoeniceus) and starling
(Sturnus vulgaris) to be greater than 100 mg/kg .

     The dietary LC5Q values for ring-necked pheasant (Phasianus
colchicus) and mallard duck (Anas platyrhynchos) exposed to 95%
technical captan are greater than 5000 ppm (Hill et al . 1975).

     Atkins et al . (1973) reports that captan is "relatively
nontoxic" to honeybees (Apis mell if era) .

     Hoyt (1969) reports that 10 days after applying captan at
0.75 lb/100 gal to apple orchards,  there  were no significant
effects on the beneficial mite, Typhlodromus occidentalis .
Croft and Nelson  (1972) determined  that  captan at 2 lb/100  gal
had "little activity" on adult female Amblyseius fallacis,
another important predaceous mite in apple orchards.  Nelson et
al. (1973) studied the toxicity of  various pesticides to a
third important predaceous mite in  apple  orchards,  Agistemus
f leschneri .  Captan, at 32 oz/100 gal was rather innocuous  to
this mite as well.

        f.  Summary of Relative Risk of  Captan to
            Terrestrial Wildlife

     Captan is relatively non-toxic to birds in dietary studies
(LCso >5000 ppm).  Data are not sufficient to address with
certainty the acute toxicity of captan to birds ( LD5Q >100  mg/kg).
However, captan is not expected to  be significantly hazardous to
birds as a result of dietary or acute exposure.  Residues on
avian foodstuffs have been calculated to  be quite low relative
to toxicity.

     Captan should pose no hazard to honey bees and other
closely related hymenopterous pollinators.

     Captan should pose no hazard to Typhlodromus occidentalis,
Amblyseius fallacis, Agistemus fleschneri and other closely
related predaceous mites.

     No statement can be made at this time concerning the hazard of
captan to mammalian wildlife.

-------
                             11-37

C.  RISK ASSESSMENT

     The risk assessment process consists of four steps.  In
the first step, Hazard Identification, all relevant information
is presented and a qualitative weight-of-the-evidence judgment
is reached on the likelihood that the pesticide is a human
carcinogen.  In the second step, Dose-Response Assessment,
experimental data are used in conjunction with certain assump-
tions and a mathematical model to extrapolate the likely upper
bound of human cancer risk to the low dose range.  The third
step is Exposure Assessment in which human exposures via various
routes and sources are estimated.  Finally, in the fourth step,
Risk Characterization, the results of the Exposure and Dose-
Response Assessments are coupled to project the plausible upper
bound of the cancer risk under different conditions of exposures.
This step also includes a summary of the strength of the
qualitative evidence, plus a treatment of the uncertainties in
the final assessment.

    1.  Hazard Identification (Qualitative Risk Assessment)

        a.  Structure-Activity Relationships

     Captan is a protectant fungicide.  The Agency has
concluded that at least two other fungicides with similar
structural relationships are oncogenic in laboratory animals.

     Folpet, also known as phaltan (N-[(Trichloromethyl)thiol]
phthalimide was administered in the diet of CD-I mice at 1000,
5000, and 12000 ppm (Chevron, 1982a).  A dose-related increase
in the incidence of intestinal adenomas and adenocarcinomas, as
well as in mucosal hyperplasia of the small intestine in both
male and female CD-I mice was observed.  These proliferative
changes occurred with the greatest frequency in the duodenum,
being more prevalent proximal to the pyloric sphincter and
decreasing with distance distally in the small intestine, as
shown by a lower frequency in the jejunum and no neoplasms, but
only mucosal hyperplasia, in the ileum.

     Captafol, also known as difolatan (cis-N-[1,1,2,2-Tetra-
chloroethy1)thiol]-4-cyclohexene-l,2-dicarboximide) has produced
tumors of a different type and location than captan [liver and
mammary gland tumors in female rats (Charles River Crl: CD
Sprague Dawley BR)  and lymphosarcomas, myeloproliferative
disease and hemangiosarcomas in both sexes of mice (CD-I)
(Chevron, 1982)].

     Since intestinal tumors were seen in the folpet-treated
but not the captafol-treated CD-I mice, it is likely that the
highly reactive electrophile, thiophosgene (the initial metabolite
derived from the one carbon side-chain of captan and folpet) is
responsible for the intestinal tumors produced by captan and
folpet.

-------
                             11-38

                                o
         I!
                         .c.     cx                /cx    II
          \           c^ ^cx \             c^    c-c
            N-SCC13    ||     I      N-SC2C14H    |      l|   ^NSCC13
         II                      II                        o
         0                      0

    Captan               Captafol                  Folpet


        b.  Metabolic and Pharmacokinetic Properties

     The metabolic an pharmacokinetic properties of captan were
discussed in section II. B. 4 of this document.

        c.  Non-oncogenic Toxicological Effects

     Over the past 30 years the acute and subacute toxicity of
captan has been studied extensively in a large number of animal
species, including rats,  swine, sheep, cattle, chicken,  hamsters,
rabbits and monkeys (EPA Substitute Chemical Program, April
1975).  These studies show that captan is not acutely toxic,
e.g., rat LDso > 5 g/kg.   In repeated dosing studies, captan
could be tolerated without ill effects at high exposure  levels.
These studies, overall, provide no additional insight on captan's
oncogenic potential.

        d.  Short Term Tests - Mutagenicity

            1)  Microbial or In vitro Cell Culture Evidence
                For the Intrinsic Mutagenicity of Captan

     Evidence (which was not rebutted) was presented in  the
Agency's PD 1 to show the ability of captan to produce mutagenic
events in bacteria, eukaryotic microorganisms, and mammalian
cells in culture.  Specifically, captan has been shown to
induce gene mutations in Escherichia coli WP2, Salmonella
typhimurium G46, TA1950,  TA1530, TA1535, TA1537, TA100,  TA 98,
and Aspergillus nidulans.  Gene mutations were also produced in
Chinese hamster ovary V-79 and lung fibroblast cells in  culture.

     An effect on DNA was indirectly shown by induction  of DNA
repair or differential toxicity in bacterial strains lacking
DNA' repair mechanisms in E^_ coli WP2, Bacillus subtil is, Asper-
gillus nidulans, Saccharomyces cerevisiae, and the following
in vitro mammalian cells in culture: SV40 transformed human
fibroblasts, Chinese hamster lung fibroblasts, and in Chinese
hamster ovary V79 cells (this last study, Tezuka et al.  1980,
was not included in the PD 1.)

-------
                             11-39

     Captan produced chromosome aberrations in cultured (in vitro)
human embryo  lung cells, rat kangaroo cells, and in Chinese
hamster ovary V79 cells  (Tezuka et al. 1980).

            2)  Reduction of Mutagenicity of Captan in the
                Presence of Liver Enzyme Systems or Free
                Sulfhydryl Groups

    In addition to the positive effects summarized above, captan
was inactive  in other studies.  In general, captan produced
mutagenic events only in the studies lacking a metabolic activation
system.  When a metabolic activation system was included the
mutagenic activity of captan was greatly reduced or undetectable.
Several studies examined this effect in detail:

    Ficsor et al. (1977) found approximately a 33% reduction in
reverse mutations in S.  typhimurium TA100 after incubation with
rat liver S9 microsomal mixture.  Similarly, Marshall et al. (1976)
found a reverse mutation reduction of approximately 50% in S.
typhimurium TA1535 and TA1537.  This decrease in activity was
also reported in the assays by Simmon et al. (1977) in S. typhi-
murium TA100 and TA1535.

    Ficsor et al. (1977) also performed host mediated assays in
which captan was injected subcutaneously in mice or given
orally to rats.  Bacteria injected intraperitoneally were later
isolated and tested for mutation induction. In another
experiment they performed, blood and urine from mice treated
orally with captan was tested for mutagenic metabolites by
means of a bacterial reverse mutation spot test.  None of these
assays showed any mutagenic activity due to the metabolized
captan.  In a final set of experiments, a reverse mutation
assay with S. typhimurium TA1535 was used to test the mutagenicity
of captan preincubated with human blood, rat blood, or rat
plasma.  In the presence of rat blood, mutagenicity was reported
at 5000 and 10,000 ug -captan/ml but not at 1000 and 500 ug captan
/ml.  The results for human blood were similar.  Mutagenicity
was seen when 20 ug captan/ml was preincubated with rat plasma
but not at a dose level of 200 ug captan/ml.

    This effect was also examined in an experiment (Moriya et al.
1978) not reported in the Position Document 1.  They found
that reverse mutations induced in E. coli WP2 her and S. typhi-
murium TA1535 by 0.15 uM captan/plate were greatly reduced or
undetected by preincubation of captan with rat liver homogenate
(both with and without the cofactors needed to activate the
enzymes),  cysteine (an amino acid with free sulhydryl groups),
or whole rat blood.   When captan was preincubated with four
concentrations of cysteine from 0.5 to 5.0 uM cysteine/uM
captan a dose response was seen (no mutagenic activity was
seen at 5.0 uM cysteine).

    Swenberg et al.  (1976) found that the activity induced by
captan in an alkaline elution DNA damage study in Chinese hamster

-------
                             11-40

lung fibroblast cells in culture was not detected in the pre-
sence of an S9 microsomal mixture metabolic activation system.

            3)  Mutagenicity of Captan in In Vivo Experiments

    No chromosome aberrations were seen in bone marrow pre-
parations after Wistar rats were given single doses of 500,
1000, or 2000 mg/kg captan by gavage or after five conse-
cutive daily doses of 200, 400, or 800 mg/kg (Tezuka et al.
1978) .

    Several dominant lethal tests were performed and all reported
negative results except for one.  Dominant lethal effects
were reported in Osborne-Mendel rats and CBA-J mice by T.F.X.

Collins (1972a).  Captan was given for 5 days by intraperitoneal
injection in doses of 2.5, 5.0, and 10 mg/kg/day or by oral
intubation in doses of 50, 100, and 200 mg/kg/day to groups
of 15 rats and 15 mice.  The mice were mated with two virgin
females each week for 12 weeks. Caesarean sections were per-
formed on the 13th day of pregnancy for the rats and on the
12th day for the mice.

     There were significant increases (p<0.05) in the number
of early fetal deaths per pregnancy among the potential off-
spring of mice given 200 mg/kg/day intraperitoneally and mated
4 and 5 weeks later.  Similar increases in the number of
early deaths per pregnancy were reported among the offspring
of mice given 100 mg/kg/day and 200 mg/kg/day orally and mated
1 and 2 weeks later.

     The groups of mice given captan at the highest doses showed
significant increases (p<0.01) in the percentage of litters
with 2 or more early fetal deaths for matings on week 5 after
intraperitoneal administration and on week 1 after oral gavage.

     Significant increases (p<0.05) were found in the mean number of
early deaths per pregnancy for those pregnancies sired by rats
4 weeks after the rats were given captan orally at a dose of
100 mg/kg/day.  Increased early fetal deaths were also found
in pregnancies sired by rats at 1, 2, and 5 weeks after treat-
ment with 200 mg/kg/day captan.  When the litter was considered
an experimental unit and affected litters were defined as those
with at least one early fetal death, a significant increase
(p<0.05)  in the number of affected litters was seen in the
rat test group given 100 mg/kg/day orally and mated after 4
weeks.   The other two dose groups showed consistent increases
in the numbers of affected litters.  In addition, there were
significant linear dose response relationships in affected litters
from rats mated 3 and 4 weeks after treatment.

     When "affected litters" were defined as those with two or
more early deaths, the data showed a significant increase (p<0.05)
in the number of affected litters for rats given a daily oral

-------
                             11-41

dose of 100 mg/kg captan and mated 2 and 5 weeks later, and
(p<0.01) for rats given a daily dose of 200 mg/kg captan, and
mated 1, 2, and 5 weeks later.

     To summarize both the rat and mouse studies (Collins,
1972a),  significant linear dose responses were seen for different
weeks of mating for various combinations of species and routes:
intraperitoneally treated rats mated in weeks 4 and 5; orally
treated rats mated in weeks 1 and 2; intraperitoneally treated
mice mated in weeks 1 to 3 and 5 to 7; and orally treated mice
mated in weeks 1 to 5 , 9, and 12.

     There are several problems with this study when considering
it for use in a risk assessment.  The direct intraperitoneal or
oral gavage exposure gives the animal an exposure that does not
relate to a dietary exposure, especially considering the
metabolic and mutagenicity (both microbial and in vitro) evidence
for reduction of mutagenic activity.-  The response is peculiar
in that no consistant pattern of spermatogenesis stage effects
are seen.  The raw data is unfortunately no longer available
to reevaluate these effects.

     Collins (1972b) also performed a 2-generation "reproduction
fitness" study in DBA/2J mice.  It was designed to show both
dominant lethal and polygenic (mutagenic) effects.  Two groups
of 110 male mice received gavage doses of 50 or 100 mg/kg of
captan for 5 days.  Each treated male was mated with 2 untreated
females for 3 weeks to produce F^ offspring, and the latter
progeny were subsequently mated to yield F2 offspring.
Significant changes induced by captan included a decreased
viability index (number newborn/total number born) in F± males
and females at 50 and 100 mg/kg; decreased weaning weights in FI
and ?2 (first litter) males and females at 50 and 100 mg/kg;
and a decreased survival index (number of survivors to day
4/number newborn) in F^ and F2 (first litter) males and females
at 100 mg/kg.

     It is difficult to make a biological interpretation of
these results.  On the basis of this test alone, it would appear
that captan could induce some type of polygenic effect in mice
although reevaluation of the data would be difficult due to
incomplete test description and lack of the raw data or parameters
such as standard error.  This particular assay in mice is highly
experimental and has not been found to be reliable.  Even X-rays,
which should provide a worst-case control, have produced
equivocal, non-reproducible, results in mice.  As in the dominant
lethal experiment (Collins, 1972a), the oral gavage dosing does
not realistically reflect the normal oral exposure.  The raw
data for this experiment is also no longer in existence.

     A study by Tezuka et al. (1978) was designed to verify the
dominant lethal Collins' study using a similar protocol in male
C3H and female SLC-ICR mice, but no dominant lethal effects
were found.  The Agency found fault with the report in the

-------
                             11-42

literature as stated in the PD 1, (the protocol was inconsistant
and unclear as reported) however additional information submitted
by Dr. Shirasu, one of the authors, shows this study to be
acceptable.  Groups of 15 male mice were treated by oral gavage
with 5 daily doses of 200 or 600 mg/kg captan.  Each male was
mated with one female at 2 to 4 days intervals.  The mating was
controlled to obtain a maximum of 2 copulated females per male
per week for 6 weeks.

     Simmon et al. (1977) in an EPA sponsored study administered
captan to ICR/SIM mice in the diet at up to 5000 mg/kg/day for
7 weeks.  No increase in the frequency of dominant lethal
mutations were seen.

     A heritable translocation study was performed by Stanford
Research Institute (SRI) for EPA (Simmon et al. 1977).  This
study was described in the PD 1.  One translocation was found
in the high dose group which would normally be sufficient to
classify captan as positive for heritable translocations;
however, one translocation was also seen in the negative control
group.  This study has been evaluated as negative, equivocal,
or positive at various times by different groups.  Since the
Position Document 1 was published, however, a committee of the
experts in the field of heritable translocation testing was
formed by EPA as part of the Gene Tox program.  This group was
charged with evaluating all heritable translocation tests
available to them.  This group of experts has evaluated the SRI
captan heritable translocation study as negative (Generoso
et al. 1980) .

     A mouse color coat spot test was submitted to the Agency
by Chevron Chemical Company as part of their rebuttal.  It was
performed by Litton Bionetics, No. 20951, October, 1980.  The
mouse spot test crosses strains of mice so that the embryos are
heterozygous for several coat-color markers.  The embryos are
exposed to the test substance in utero by treating females
during gestation.  Mutations induced in these heterozygous
melanocyte somatic embryo cells may be manifested (as the cells
develop into clones on the skin) as variously colored spots on
the newborn mice. These mutations may be due to both chromosome
damaging or gene mutational mechanisms.

     T-strain males, genotype (a/a,b/b,ccnp/cchp,d se/d se, s/s)
from Oak Ridge National Laboratory Tennessee were mated daily with
2 female C57BL/6J mice, genotype (a/a), from Charles River,
Wilmington, MA.  Mating was continued until sufficient females
were obtained for the experiment.

     Fifty to fifty-two pregnant female per group were treated
with 0,  100, 1000 and 5000 ppm captan in the diet on days 8, 9,
10, 11,  and 12 of gestation.  Twenty six females were treated
with ethylnitrosourea (ENU) as the positive control group.  The
incidences of recessive somatic mutation spots were 2.9, 4.4,
2.2, and 1.9% respectively for 0, 100, 1000, and 5000 ppm

-------
                             11-43

captan.  ENU induced 19.4% recessive somatic mutation spots.
This study may be considered negative for captan.

            4)  Risk of Heritable Mutations

     In order to have concern for transmission of heritable
mutagenic events, it must be shown that:

     (a) The chemical is an intrinsic mutagen; e.g. that
         it is able to affect DNA and cause a mutagenic event.

     (b) The chemical is able to reach the gonads in an
         active form.

     (c) Mutations induced in gonadal cells are transmitted
         through offspring.

     In the case of captan, it  is evident that it has intrinsic
mutagenic properties.  This mutagenicity, however, is diminished
or absent in vivo at normal exposure levels.

     The mutagenic endpoints of concern for captan are gene mutations
and chromosome aberrations.  For gene mutations, captan has
been demonstrated to have intrinsic mutagenicity in microbial
systems and in in vitro cell assays.  In a relatively sensitive
in vivo system (the mouse coat  color spot test), however, no
mutagenicity was detected.  This is one of the few in. vivo systems
which will detect gene mutational events.  It is a somatic cell
system and is not capable of determining if a mutation is
heritable.  The only other test that could be performed at this
stage in order to assess gene mutational heritable risk is the
mouse specific locus test.  The mouse specific locus test is
less sensitive than the spot test when performed with any
reasonable number of animals; therefore, it is not expected to
detect any mutational events with captan.

     For chromosome aberrational events, the dominant lethal
test is capable of detecting mutations in gonadal cells in the
male.  A positive dominant lethal test shows that the chemical
reaches the gonads in an active form.  Equivocal results are seen
in these tests for captan.  All of the well conducted tests
are negative; however, the Collins' dominant lethal tests were
reported as positive.  The Agency does not have complete confidence
in these results, but for the purposes of this risk assessment,
it is provisionally considered  as a positive test. To assess
heritable risk, it must now be  determined if the mutational event
may be transmitted to future generations.  The best developed
assay available to us is the heritable translocation test.
The dominant lethal assay does  not reveal heritable events since
the event measured is lethality and is therefore not usable
for quantitative risk assessment.  The heritable translocation
test has been shown to be negative.

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                             11-44

     Captan has been shown to be mutagenic in in vitro experiments
in lower organisms, but the results are equivocal in the in vivo
experiments.  The Agency concludes that captan is either non-
mutagenic J.TI vivo or possesses such a low mutagenic capacity in
the in vivo assays used for quantitative heritable mutagenic
risk assessment that it is not possible to detect its mutagenic
activity.  Although captan may be able to cause somatic mutational
events and may, therefore, have an oncogenic problem, the risk
to humans of heritable mutagenicity is extremely low or does
not exist and does not warrant further testing at this time.

        e.  Long-Term Animal Studies - Oncogenicity

            1)  Summary of Pertinent Studies in Animals

     The analysis of three captan chronic feeding studies
showed a dose-tumor relationship yielding an average (geometric
mean) potency of Q^* = 2.3 x 10~3 (for dose in mg/kg/day)
with a weight of evidence classification B2 (probable human
carcinogen) under the draft EPA guidelines (U.S. EPA, 1984,
49 FR 46294).  This potency factor is based on adenomas and
adenocarcinomas of glandular cell origin in the gastrointestinal
tract of both sexes of mice in three studies and on kidney
tumors in male rats.

               (a) Innes et al. (1969)

     Innes et al. (1969) studied 120 chemicals and 10 control
compounds which were tested in two hybrid strains of mice.
Eighteen mice/strain/compound were administered the maximum
tolerated dose (MTD) by gavage from day 7 to day 21.  The study
mice were then fed test or control compound mixed in with their
daily diet until death or sacrifice, at 18 months of age.  The
captan treated mice were administered 215 mg/kg/day by gavage
and later 560 ppm in their diet.  No increase over control
incidence of liver, lung, or lymphoid cell tumors was detected
at the pjŁ .05 level of statistical significance.

               (b) National Cancer Institute (1977)

     The National Cancer Institute (1977) study, "Bioassay of
Captan for Possible Carcinogenicity" was conducted by Gulf
South Research Institute using 50 animals per treated group and
10 concurrent controls per sex per species of B6C3F1 mice and
Osborne-Mendel rats.  The dosing schedules followed for mice
are found in Table 1.

     The NCI report evaluated the B6C3F1 mouse pathology findings
as quoted below (excerpts from NCI (1977) pp. 27 and 29-31).

     "With the exception of the proliferation and/or neo-
      plastic lesions observed in the duodenum of both
      male and female treated mice, the pathological changes

-------
                               11-45
       Table 1 - Design of Captan Chronic Feeding Studies in
B6C3F1 Mice (NCI, 1977)

Sex and
Treatment
Group
MALE
Matched-Control
Low- Dose
High-Dose
FEMALE
Matched-Control
Low-Dose
High-Dose

Initial
No. of
Animals3
10
50
50
10
50
50

Captan
in Diet
(ppm)
0
8,000
0
16,000
0
0
8,000
0
16,000
0

Time on Study
Treated Untreatedb
(weeks) (weeks)
91
80
11
80
11
90-91
80
11
80
11
aAll animals were 35 days of age when placed on study.

bwhen diets containing captan were discontinued, all treated mice
 and their matched controls were fed the control diet (2% corn oil
 added) until termination of the study.

-------
                            11-46

     observed were not considered to be related to the
     administration of captan.

     The duodenum lesions were located approximately 1 cm
     posterior to the pylorus,  usually in the antimesenteric
     portion of the duodenal muscosa.   Grossly, they
     were either single,  well-circumscribed (3-5 mm
     across) and slightly elevated (1-2 mm) areas, or
     single, thin mucosal projections  up to 5 mm in
     height.  The lesions were inconspicuous on the
     serosal surface.  Microscopically, the following
     three different lesions were classified:

        (1) mucosal hyperplasia — a proliferation of
     glands and villi epithelium,

        (2) adenomatous polyp -- a more accentuated
     proliferative process with glandular structures and
     villi aggregated and branched around supporting
     stalks made up of connective tissue (features of
     malignancy were not observed), and

        (3) adenocarcinoma (polyploid carcinoma) -- one of
     the most advanced and aggressive-appearing lesion,
     consisting of cellular anaplasia with numerous mitotic
     figures, disorganized microacini, and areas where focal
     neoplastic infiltration was evident.

     Tinctorial changes (basophilia) were also present.

     The classification of these lesions was frequently
     difficult.  Nevertheless,  the location and some
     common cellular characteristics suggest that they
     are different development stages  of the same type
     of lesion.  The distribution and incidence of the
     duodenal alteration were as follows:

                     	Male Mice	Female Mice
                               Low   High             Low   High
                     Controls  Dose  Dose   Controls  Dose  Dose

Number examined        (9)     (43)  (46)     (9)     (49)  (48)
Adenocarcinoma          0        13       0        03
Adenomatous polyp       0        22       1        10
Mucosal hyperplasia     0        03       0        00

     The rarity of these lesions in the strain of mouse
     used suggests that the lesions were caused by captan.

     The incidences of adenocarcinoma of the duodenum showed a
     significant linear trend for both male and female mice,
     with Cochran-Armitage probability levels of 0.033 and
     0.022, respectively, using the pooled controls.  The Fisher
     exact test results for both sexes are not significant.

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                             11-47

      When the incidences of adenocarcinoma of the duodenum are
      combined with those of adenomatous polyp, not otherwise
      specified, for statistical analysis, the tests for male
      mice show a substantial increase in significance when
      compared with pooled controls.  The test for positive
      linear trend is significant  (P = 0.008), the Fisher Exact
      Test in the high dose male mice has a probability level
      of 0.009, and the 95% confidence interval for relative
      risk has a lower limit of 1.849 using pooled controls.
      The incidence of these combined tumors in female mice is
      not significant.  The overall consideration of these
      various statistics suggests  a dose association of the
      test chemical with tumors in the duodenum in male mice."

Table 2 presents the design of the chronic feeding study in rats.
In NCI's evaluation of the Osborne-Mendel rat pathology, they
state:

      "In rats, there was a positive dose-related trend
      (P = 0.047) for the combined incidence of cortical
      adenoma and the cortical carcinoma of the adrenal
      gland in high-dose females compared with the incidence
      in the pooled controls... (pooled controls 0/64, low
      dose 2/50, high dose 3/47)....  However, the spontaneous
      incidence is variable in this strain of rat, and the
      incidence of tumors was very low; one adrenal cortical
      adenoma and one carcinoma were found in the low-dose
      animals and two adrenal cortical adenomas and one
      carcinoma in the high-dose group.  There was also a
      positive dose-related trend  for the incidence of C-
      cell adenoma of the thyroid  in female rats (pooled
      controls 1/66, low-dose 1/49, high-dose 4/44, P =
      0.035).  The relationship of these tumors to treatment
      is not clearly established."

     The individual animal data of this study have not been
reviewed to verify the NCI report  tables or statistics, either
by Chevron or by the Agency.  The  findings in the mouse were
considered by Chevron to be an unusual or false positive finding.
Accordingly, Chevron replicated the NCI study in a different
strain of mouse.

               (c)  High-Dose Mouse Study (HDS) (Chevron, 1981)

     The Chevron (1981) study differed from the NCI (1977)
study in several respects: the average daily dose differed
slightly; the dosing schedule was  increased at week 5 of the
study and continued at the revised level until planned kill
after 113 weeks of feeding (when the animals were approximately
120 weeks of age);  and CD-I mice were used as the experimental
animal.   The experiment was performed at a different laboratory
so that all environmental factors  and study personnel differed.
There were 80 animals per sex per  dose including 80 concurrent
controls per sex.  The study design is found in Table 3.  The

-------
                              11-48
  Table 2 - Design of Captan Chronic Feeding Studies in Rats (NCI, 1977)
Sex and
Treatment
Group
MALE

Matched Control3

Low Dose



High-Dose
Initial
No. of
Animalsb
  10

  50



  50
FEMALE

Matched-Control3      10

Low-Dose              50



High-Dose             50
Captan
in Diet
 (ppm)
    0

4,000
2,000
    0

8,000
4,000
    0
               0

           4,000
           2,000
               0

           8,000
           4,000
               0
  Time on Study
Treated Untreated
(weeks)0 (weeks)^
Time-Weighted
Average Dose6
    (ppm)
  21
  59
  41
  39
             21
             59
             41
             39
           114
            33
                                                      34
                      114
                       33
                                                      34
    2,525
                                                                  6,050
                        2,525
                                                                  6,050
3The matched controls consisted of 5 animals of each sex, started
 with the low-dose animals, and 5 animals of each sex, started with
 the high-dose animals.

t*All animals were 35 days of age when placed on study.

cDoses of captan were lowered at week 21 during the study, since
 it was believed that excessive mortality might occur before
 termination of the study based on the mortality, weight changes,
 and general condition of rats used in similar bioassays of
 other chemicals at Gulf South Research Institute.

dWhen diets containing captan were discontinued, the high-dose rats
 and their matched controls were fed the control diet without
 corn oil for 6 weeks, then the control diet (2% corn oil added)
 for an additional 28 weeks, while low-dose rats received only the
 control diet (2% corn oil added) until termination of the study.

eTime-weighted average dose = (dose in ppm x no. of weeks at that dose)
                              (no. of weeks receiving each dose)

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                            11-49

    Table 3 - High-Dose Mouse Study Design (Chevron, 1981)

Group     Dose  (ppm) Weeks 1-4  Weeks 5-113    Time Weighted Average
I
II
III
IV
     0
 2,000
 6,000
10,000
     0
 6,000
10,000
16,000
     0
 5,858
 9,858
15,788
pathologist  (W.L. Spangler) used the terminology "adenoma" and
"adenocarcinoma" to designate the benign and malignant forms of
duodenal and other intestinal neoplasms of glandular cell
origin.

     During  the HDS, no unusual diseases or complicating
factors were observed.

     Survival appears dose-related as can be seen from the
"at risk" mortality data given in Table 4.

Table 4 - High-Dose Mouse Study Mortality Rates (Chevron, 1981)

         (Number of Deaths/Number of Animals at Risk)

                            MALES
Time Interval
(weeks)
0-52
53-75
76-90
Survivors
Dose (ppm)
0
5/80
9/75
14/66
52
6,000
3/80
12/77
8/65
57
10,000
4/79
16/75
12/59
47
16,000
8/80
16/72
28/56
28
                           FEMALES
Time Interval
(weeks)
0-52
53-75
76-90
Survivors
Dose (ppm)
0
4/80
8/76
17/68
51
6,000
3/80
6/77
11/71
60
10,000
4/80
5/76
10/71
61
16,000
4/80
17/76
30/59
29
     In males there is a statistically significant dose related
trend in mortality which is best demonstrated by examining
dosed animals only.  The survival pattern of females is less
clear but is still statistically significant due to the higher

-------
                            11-50

mortality in the high dose (16,000 ppm) group.  Using Peto's
trend test (Peto, 1980) P < .0001 for males and .0003 for
females.

     With respect to the duodenal tumors, the Chevron (1981)
report shows the following in their "Table 4" (Volume I of
VII of the Chevron report):

                           "Socal Table 4"
Duodenum
Number Examined3/
Number with duo-
denal neoplasms
Adenocar cinemas*3/
Adenoma^/
Undifferentiated
Sarcoma
Males
Control
74
2
1
1
0
Low
73
20
10
11
1
Mid
72
21
14
7
0
High
75
39
30
11
0
Females
Control
72
2
0
2
0
Low
78
24
17
10
0
Mid
76
19
14
8
0
High
76
29
20
12
0
a/  Excluding severely autolyzed and missing tissues.

b/  Tabulated by total number of neoplasms? some animals had
    multiple  (i.e., both benign and malignant) neoplasms.

Note: the doses are Control = 0; Low = 6000 ppm; Mid = 10000 ppm;
      and High = 16000 ppm.
     The Agency review of the individual mouse data reveals
that while there were a number of animals where gastrointestinal
tract tissue was autolyzed, the Socal pathologist, Dr. W.L.
Spangler, was able to diagnose pathological changes when they
were present.  Therefore, the denominators used in this report
exclude only animals where digestive tract tissue was reported
as missing.  Secondly, the 19 individual animals among the low-
dose males were diagnosed with adenoma or adenocarcinoma of the
duodenum - the 20th mouse reported in this study had only an
undifferentiated sarcoma.  The 19 included 8 animals with
adenocarcinomas only, 9 with adenoma only and 2 with both.

     Statistical evaluation of the adenoma-adenocarcinoma
incidence data from the High-Dose study showed statistically
significant dose related trends in both sexes for the summary
data displayed in "Socal Table 4" and for the time-weighted
trends of these findings.  The Exact Test also indicates that
the incidence in all treated groups is statistically greater,
P<.01, than the incidence observed in the control group.

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                            11-51
                (d) Low-Dose Mouse Study  (LDS)(Bio/Dynamics, 1983)

     The primary purpose  of this study  (done  by Bio/dynamics,
1983,  for Chevron) was  to characterize  the response of the
gastrointestinal tract  to captan in mice.  This is illustrated
by the  restricted  number  of tissues taken and the detailed
specific instructions for removal, handling, preparation for
gross  and microscopic examination of  the entire gastrointestinal
tract.  Test  animals were Charles River  CD-I mice (ICR derived).
The experimental design utilized five dose levels (0, 100,
400, 800, 6,000 ppm) of captan with 100 mice of each sex
being  randomly  assigned to each dose  level.  No unusual
diseases or complications were observed.

     Although there was an unusually  high mortality among
control animals, there  is evidence of a mortality-dose related
trend  (but not  as  strong  as in the HDS).  These findings are
shown  in Table  5.

Table  5 - Low-Dose Mouse  Study Mortality Rates (Bio/Dynamics, 1983)
        (Number of Deaths/Numbers of  Animals at Risk)

                            MALES
Time Interval
(weeks )
0-52
53-75
73-88
Survivors
Dose (ppm)
0
7/100
38/93
23/55
22
100
4/99
32/95
32/63
31
400
4/100
24/96
43/72
29
800
5/100
31/95
32/64
32
6,000
13/100
54/87
24/33
9
                           FEMALES
Time Interval
(weeks )
0-52
53-75
73-88
Survivors
Dose (ppm)
0
12/100
22/88
24/66
42
100
6/100
22/94
26/72
46
400
4/100
17/96
32/79
47
800
8/100
16/92
26/76
50
6,000
3/100
28/97
29/69
40
     Using Peto's trend test  (Peto, 1980) on the above data
shows a statistically significant dose related increase in
male mortality rates, P<,01;  but no important effect among
females, P<.21.

-------
                                 11-52
0
          Although this study was planned to run for two years
     (104 weeks)  it ended at about 96 weeks due to the poor survival.
     However,  the tissues from the gastrointestinal tract of all
     animals were examined.   Separate tables were provided by
     Knezevich for hyperplastic lesions of the duodenum (Bio/Dynamics
     Table A)  and jejunum/ileum (Table B);  and neoplastic lesions
     characterized as "adenoma/polyp(s)",  "carcinoma primary",
     "squamous cell carcinoma", and leiomyosarcoma" of the stomach
     (Table C),  duodenum (Table D), jejunum/ileum (Table E), and
     cecum/colon (Table F).   No discussion was provided by Bio/dynamics
     of the overall gastrointestinal response but animals appearing
     in two places on one table or in multiple tables were identified.
     These tables are not reproduced in this document.

          In reviewing the data from this study, the Agency followed
     the guidance by National Toxicology  Program (NTP) scientific
     counselors report (NTP, 1984).  Only animals with adenoma or
     adenocarcinoma (carcinoma) of the glandular cells were used,
     moreover, to make the data in this report comparable with the
     high-dose study the 2 females with cecum or colon polyp or
     carcinoma were omitted.  One of these,  the control female
     with carcinoma could not be verified by examination of the
     raw data (i.e., individual animal pathology studies).

          The Agency recount of animals with adenoma/polyp and/or
     carcinoma of glandular cells of the  gastrointestinal tract
     are shown in Table 6.

     Table 6 - Diagnosis of Gastrointestinal Tract Glandular
               Tumors for Stomach, Duodenum, and/or Jejunum/ileum
               (Bio/Dynamics, 1983)
     Females
100
400
              Diagnosis

800   6,000  Dose Groups
0
                                            Males
100
400
800   6,000
0/100  1/100 3/100 3/100 5/100  Adenoma/polyps  0/100  6/100  1/100  1/100 4/100
0/100  0/100 0/100 0/100 2/100  Carcinoma	0/100  0/100  0/100  0/100 1/100
0/100  1/100 3/100 3/100 7/100  Either
                                         0/100  6/100  1/100  1/100  5/100
          The incidence of adenoma and carcinoma  of  the  glandular
     cells of the gastrointestinal tract demonstrated a  statistically
     significant dose-related response (P<0.01)  in female  rats.
     In addition, the Fisher's Exact Test comparing  high-dose
     incidence with controls shows a statistical  significance of
     P<0.025 in females.   However, in males no dose  response trend
     was noted.  The Fisher's Exact Test comparing the 100 ppm group
     with controls shows a statistical significance  of P<0.05.

                    (e) Rat Study (RS) (Stauffer/Chevron,  1982)

          This study was carried out by E.F.  Goldenthal  and
     L.W. Nelson of the International Research and Development

-------
                            11-53
Corporation  (IRDC)  for Stauffer Chemical Company starting
October 4, 1978, and terminating 2 years later on October 3,
1980  (Stauffer/Chevron,  1982).  Test animals were Charles
River CD  rats.

     The  experimental design specified four dose levels (0, 20,
100, 250  mg/kg/day) of captan fed to 70 rats of each sex per
level for a  duration of  2 years.  No unusual diseases or compli-
cations were observed.   The survival rates are of interest.
Table 7 shows  the results of the rat survival and mortality
rates in  this  study.

    Table 7  -  Rat Study  Mortality (Stauffer/Chevron, 1982)
        (Number of  Deaths/Numbers of Animals at Risk)

                            MALES
Time Interval
(weeks )
0-52
54-78
80-88
90-96
Survivors
Dose (ppm)
0
2/70
5/58
3/43
4/40
36
25
3/70
3/57
4/44
7/40
33
100
3/70
3/57
6/44
7/38
31
250
3/70
9/57
5/38
7/33
26
                           FEMALES
Time Interval
(weeks )
0-52
54-78
80-88
90-96
Survivors
Dose (ppm)
0
2/70
1/58
4/47
4/43
39
25
1/70
7/59
7/42
6/35
29
100
1/70
3/59
4/46
5/42
37
250
3/70
7/57
2/40
3/38
35
     There is a statistically significant, P<.025, dose
related trend in mortality for males but not for females
(Peto's test for trend).

     In the male rats, the data demonstrate a statistically
significantly increasing trend for kidney tumors (benign and
malignant combined), 1/70 controls, 1/70 fed 25 mg/kg/day,
3/70 fed 100 mg/kg/day, and 4/70 fed 250 mg/kg/day; as shown

-------
                                11-54

    by the Armitage trend test P<.05.  The results of the findings
    are shown in Table 8, which indicates that progression to
    malignancy was not predominate.

Table 8 - Summary of Pathology in Captan Long-Term Feeding Studies - Rats

NCI - Osborne Mendel Rats (NCI,1977)

Dose in ppm             _0	   6000   16000

Adrenal Cortical    (F) 0/64   2/50   3/47
adenoma or carcin-  (M) 0/65   0/47   1/47
oma

Thyroid C-cell      (F) 1/66   1/49   4/44
adenoma             (M) 2/65   1/42   1/47


IRDC - Charles River, CD Male Rat (RS) (Stauffer/Chevron, 1982)

Dose in ppm	0	25	100	250

Kidney Cortical Cell and/or Tubular Cell Tumors in Males

Ademomas                  1023

Carcinomas	0	1	1	1

Totals                 1/70    1/70     3/70     4/70

         Table 9 shows the total number of animals with tumors of
    the glandular cells of the gastrointestinal tract, as recommended
    by the Board of Scientific Counselors, National Toxicology
    Program, in Appendix V of their report, "Report of the NTP Ad
    Hoc Panel on Chemical Carcinogenesis Testing and Evaluation,"
    August 17, 1984 (NTP, 1984).

         The Agency notes that the tumor response is more significant
    at the 6000 ppm dose for the Socal high-dose study than in
    the Bio/Dynamics low-dose study.  This may reflect a marked
    difference in the dosing schedules of the two studies.  Never-
    theless, the low-dose study demonstrates a significant increase
    in the same rare gastrointestinal tumors.

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                                11-55


Table 9 - Summary of Pathology in Captan Long-Term Feeding Studies - Mice


    Dose in ppm	0     100    400     800    6,000  10,000  16,000

NCI - B6C3FI Mouse (NCI, 1977)

Duodenum
Adenocarcinoma      (F) 0/68   -                      0/49    -      3/48
                    (M) 0/68   -                      1/43    -      3/46

Socal High-Dose Study CD-I Mouse (Chevron, 1982a)

Adenoma or adeno-
carcinoma of        (F) 3/80   -                      26/80  21/80  29/80
gastrointestinal    (M) 3/80   -                      19/80  22/79  39/80
tract

Low-Dose Study, CD-I Mouse (Bio/Dynamics, 1983)
Adenoma/polyp or
carcinoma of the
gastrointestinal
tract
(F)
(M)
0/100
0/100
1/100
6/100
3/100
1/100
3/100
1/100
7/100
5/100
            f.  Human Studies

         The Agency is unaware of any human studies that have
    investigated the oncogenicity of captan.

            g.  Weight-of-the-Evidence

         The goal of the Hazard Identification step of the Cancrr
    Risk Assessment is to reach a qualitative judgement on the
    evidence that captan may be a human carcinogen.

         The data show that captan has demonstrated statistically
    and biologically significant oncogenic responses in both
    sexes of mice and in male rats.  Tumors, including adenocarcinomas,
    of the digestive tract were observed in both sexes of mice in
    three studies.  Although negative results were reported for
    Sprague Dawley rats in a 2-year study submitted by Makhteshim
    Chemical Works, Ltd. Beer-Sheva, Israel (1983), kidney tumors
    were observed in Charles River CD male rats in the IRDC study

         As further supporting evidence, captan is structurally
    similar to folpet and captafol which have demonstrated oncogenic
    effects in laboratory animals.  Of primary importance, folpet
    has induced intestinal tumors, including adenocarcinomas in
    mice (Chevron, 1978 and 1982a).  Captan also induces intestinal
    adenocarcinomas in mice; this type of tumor is quite rare in
    rodents.  Captafol produced a dose-related increased incidence

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                            11-56

of fibroadenomas of the mammary gland and an increased incidence
of neoplastic nodules in the liver of the female rat and lymph-
osarcomas, myeloproliferative disease, and hemangiosarcomas in
both sexes of mice (Chevron, 1982).  However, as these tumors
were not seen in captan treated mice, they are not as significant
as the intestinal adenocarcinomas induced by folpet.

     As discussed in detail above, in section Il.C.l.d., captan
has been demonstrated to be mutagenic in microbial systems and
in in vitro cell assays.  Captan produced chromosome aberrations
in cultured (in vitro) human embryo lung cells, kangaroo rat cells
and in Chinese hamster ovary V79 cells.  In general, captan pro-
duced these mutagenic events only in the studies lacking a meta-
bolic activation system.  When a metobolic activation system was
included the mutagenic activity of captan was greatly reduced or
undetectable.  Captan is either non-mutagenic in in vivo assays
or possesses a low mutagenic capacity.  -The in vitro tests as
performed using captan present many more target sites for potential
mutation detection than do the in vivo tests.  In addition, the
cells examined for mutagenic effects in the in vivo tests are not
those in which oncogenic effects were seen.  For these reasons,
the lack of detectable mutagenic effects in the in vivo assays
does not preclude the possibility that captan may be genotoxic
and may induce tumors, particularly at the initial site of metab-
olism in the intestines.

     The Agency concludes that captan is a demonstrated animal
oncogen.  There are no data available concerning direct
evidence of oncogenic effects in humans.  Therefore, the
Agency takes the position that captan should be viewed as
having the potential to be a human oncogen.  In the context
of the categorization adopted by the Agency's modification of
the International Agency for Research on Cancer (IARC) class-
ification scheme (U.S. EPA, 1984), captan has been assigned
to category B2, a probable human carcinogen.

     2.  Dose Response Assessment

     The analysis of the rat data focuses on kidney adenomas
and carcinomas while the corresponding work for mice also
counts adenomas and adenocarcinomas of the stomach, duodenum,
and jejunum-ileum.  The rationale for combining these organ
sites and tumor types in the mouse studies is outlined in the
National Toxicology Program - Board of Scientific Councillors
Meeting, September 23 and 24, 1982 (NTP, 1982).

     The tumor data are summarized in Table 8.  Statistically
significant increases in adenomas (benign) and adenocarcinomas
(malignant) of the gastrointestinal tract of male and female
mice and kidney tumors in male rats were found.

     The Agency has used the linearized Multi-stage model for
risk assessment purposes for the reasons discussed in the
Agency's Proposed Guidelines (U.S. EPA, 1984, 49 FR 46294).

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                            11-57
There is currently no compelling biological rationale for
using any particular model.  The Multi-stage model provides a
consistently adequate fit to both male and female tumor data
and it appears to be the most stable estimator.  The Multi-stage
model is stable with respect to the data in that minor changes
in the input data cause little or no change in model parameters
such as QI*(potency).  Consider the following potencies (Qi*):
        male mice HDS
        male mice LDS
        female mice HDS
        female mice LDS
        male rats
3.9 x 10-3 (mg/kg/day)-1
1.0 x 10-3 (mg/kg/day)-1
3.4 x 10-3 (mg/kg/day)-1
2.0 x 10-3 (mg/kg/day)-1
2.4 x 10-3 (mg/kg/day)-1
All of the QI* values are tightly grouped.  Assuming that
the distribution of the QI*  is a positive random variable but
is otherwise unknown, and if the tight grouping of the Q^*'s
is indicative of the true value, then a reasonable way to
pool the values is to estimate an overall Q]_* by the geometric
mean.  This gives the value  of Q-^ * = 2.3 x 10~3 (mg/kg/day)"1.

     The estimates of QI* presented above represent the upper
95% bound on the QI* .  The lower limit of the QI* approaches
zero.

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                             11-58

    3.  Exposure Analysis

     Captan (N-trichloromethylthio-4-cyclohexene~l,2-dicarbimide)
is a fungicide registered for use to control a wide variety of
fungal diseases on fruit, vegetable, field and ornamental
crops; seeds; wooden packing house boxes; in soils; walls of
homes; cosmetics; Pharmaceuticals; oil based paints; lacquers;
paper; wallpaper paste; plasticizers, polyethylene; vinyl;
rubber; textiles; and in combination with insecticides on crops,
seeds, and household pets.  Captan is formulated as wettable
powders, flowables, dusts, and granules.  It is an ingredient
in approximately 600 pesticide products registered in the
United States.  The entire U.S. population may be exposed to
captan residues through the diet from eating food crops which
have been treated with captan.

        a.  Agricultural Uses

           (1) Applicators and Mixer/Loaders

     When work on the captan PD 2/3 began, the Agency limited
the non-dietary exposure analysis to 7 representative use
sites.  The sites included apples, strawberries, home gardens,
almonds, apples, potatoes, and soybeans.  These sites were
chosen because one or more of the following criteria applied:
(1) a high volume use; (2) a high percent of crop treated; (3)
availability of a good captan exposure study or surrogate
study; and (4) the potential for high exposure.

     The Agency determined that these estimated risks were high
enough to merit looking at all sites to see if the risks from
these remaining sites were in the same order of magnitude,
higher, or possibly lower.  The results are summarized in
Tables 10 and 11.

     A discussion of the assumptions used to estimate non-dietary
exposure and a discussion of the results follow (Day, 1984a and
Jensen, 1982).

         (1)  FRUIT CROPS - FOLIAGE AND PRE-HARVEST USES

     Generally captan is applied as a 50% wettable powder (WP)
to fruit crops.  Low- or high-volume ground air-blast equipment
is used.  From 2 to 15 applications are made per year, with
mixing/loading and application taking from 4.0 to 6.5 hours at
approximately 7 day intervals.

     For certain application methods, the Agency has an extensive
data base available for use in estimating applicator exposure.  In
such instances, the Agency's policy is to use this generic data
base for exposure assessments rather than the results of
individual studies conducted with a limited number of replicates
(Reinert and Severn, 1985).

-------
Table 10 - Non-Dietary Exposure Estimates for Mixer/Loaders
Fruit
Crops
Almond s^/
Apples
(pre-harvest)
Apples
(post-harvest)
Apricots
Avocado
Blackberry
Blueberry
Cherries
Citrus
Cranberry
Grapes
Mangos
Nectarine
peaches
Pears
Plum
Pineapple
Vegetable Crops
Beans
Beets
Carrots
Celery
Curcurbits
Bggplant
Lettuce
Peppers
Potatoes (foliar)
AI/A.
Rate
_^

3

-
4
4
1
1
4
4
4
1.5
5
5
5
2.5
3
2

2.5
2.5
2.5
5
2
2
2.5
2.5
4
Hrs
Day
_

0.5

0.25
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5

0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
Hrs.
Yr.
_

5

7.5
2
2
2.5
5
5
1
1.5
3
6
2.5
2.5
3
3.5
13

4
3.5
4
6.5
6.5
7
4
10
8.5
Max.
Appl.
Number
Season
_

10

30
4
4
5
10
10
2
3
6
12
5
5
4
7
26

8
7
8
13
13
14
8
20
17
Exposure
Hourly
Dermal Inhalation
8001/

180

180
180
180
180
180
180
180
180
180
180
180
180
180
180
180

180
180
180
180
180
180
180
180
180
3.2V

6

6
6
6
6
6
6
6
6
6
6
6
6
6
6
6

6
6
6
5
6
6
6
6
6
in ng

Yearly
Dermal Inhalation
1600

900

1100
360
360
450
900
900
180
270
540
1100
450
450
540
630
2300

720
630
720
1200
1200
1300
720
1800
1500
6.4

30

45
12
12
15
30
30
6
9
18
36
15
15
18
21
78

24
21
24
39
39
42
24
60
51
                                                                                                    I
                                                                                                    en

-------
Table 10 (continued)

Potatoes
( seed treatment )
Rhubarb
Soybeans
(seed treatment)
Spinach
Sweetcorn
Tomatoes
Ornanentals
Azaleas
Begonias
Carnations
Mums
Diconda(CA)
Turf
Roses
Flowers
AI/A.
Rate

-
4

-
4
4
4

2
2
2
2
2
2
2
2
Hrs
Day

0.44
0.5

0.25
0.5
0.5
0.5

0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
Hrs.
Yr.

2.2
5

0.5
2
5
6.5

2
6
10
10
1.5
10
10
7.5
Max.
Appl.
Number
Season

5
10

2
4
10
13

4
12
20
20
3
20
20
15

"^fcposure
Daily
Dermal Inhalation

8
180

8
180
180
180

180
180
180
180
180
180
180
180

1
6

1
6
6
6

6
6
6
6
6
6
6
6
in mg

Yearly
Dermal Inhalation

41
900

19
360
900
1200

360
1100
1800
1800
270
1800
1800
1400

3.5
30

2
12
30
39

12
36
60
60
9
60
60
45
I/
Assumes 800 Ibs captan/day are loaded and a/erage dermal and respiratory  exposure  are
1 mg and 0.004 mg per Ib of captan loaded.

-------
Table 11 - Non-Dietary Exposure Estimates for Applicators
Fruit
Crops
Almonds 2
Apples
Apricots
Avocado
Blackberry
Blueberry
Cherries
Citrus
Cranberry
Grapes
Mangos
Nectarine
Peaches
Pears
Plum
Pineapple
Vegetable Crops
Beans
Beets
Carrots
Celery
Cucurbits
Eggplant
Lettuce
Peppers
Potatoes (foliar)
Potatoes
(seed treatment)
Rhubarb
Spinach
Strawberries
AI/A.
Rate
.5-6
3
4
4
1
1
4
4
4
1.5
5
5
5
2.5
3
2

2.5
2.5
2.5
5
2
2
2.5
2.5
4

-
4
4
3
Hrs
Day
4
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6

6
6
6
6
6
6
6
6
6

5.6
6
6
1
Hrs.
Yr.
8
60
24
24
30
60
60
12
18
36
72
30
30
24
42
156

48
42
48
78
78
84
48
120
102

33
60
24
10
Max.
Appl.
Season
2
10
4
4
5
10
10
2
3
6
12
5
5
4
7
26

8
7
8
13
13
14
8
20
17

5
10
4
10
(1)
Appl.
Mode
A
AB
AB
AB
GB
GB
AB
AB
GB
GB
AB
AB
AB
AB
AB
GB

GB
GB
GB
GB
GB
GB
GB
GB
GB

-
HS
GB
GB

Exposure
Hourly
Dermal Inhalation
2.27
30
35
35
24
24
35
35
24
24
40
40
40
28
30
24

24
24
24
24
24
24
24
24
24

0.35
1.7
24
24
nag .
0.06
0.06
0.06
0.06
0.06
0.06
0.06
0.06
0.06
0.06
0.06
0.06
0.06
0.06
0.06

0.06
0.06
0.06
0.06
0.06
0.06
0.06
0.06
0.06

0.03
0.0017
0.06
0.06
in mg

Yearly
Dermal Inhalation
18
1800
840
840
720
1440
2100
420
430
860
2900
1200
1200
670
1300
3740

1150
1000
1150
1870
1870
2000
1150
2900
2400

10
100
580
240
neg.
1
1
1
2
4
4
1
1
2
4
2
2 ^
o *
3 ""
9

3
3
3
5
5
5
3
7
6

1
0.1
1
1

-------
Table 11 (continued)
Max. (1)


Sweet corn
Tomatoes
Homegardens
Ornamentals
Azaleas
Begonias
Carnations
Mums
Diconda(CA)
Turf
Roses
Flowers
(1) The following
AI/A.
Rate
4
4
-

2
2
2
2
2
2
2
2
exposure
Method Abbre vi at ion
airblast AB

ground GB
handspray HS
aerial A





Hrs
Day
6
6
1.2

6
6
6
6
6
6
6
6
values
Hrs.
Yr.
60
78
5

24
72
120
120
18
120
120
90
by method
Appl . Appl .
Season Mode
10
13
4

4
12
20
20
3
20
20
15
are:
Dermal mg/hr
4.8

24
1.7
2.27
(Rate)+ 16









GB
GB
HS

GB
GB
GB
GB
GB
GB
GB
GB
•
»
Respiratory mg/hr
0.06

0.06
0.0017
neg.
Exposure in
Hourly
Dermal Inhalation
24 0.06
24 0.06
1.7 0.0017

24 0.06
24 0.06
24 0.06
24 0.06
24 0.06
24 0.06
24 0.06
24 0.06

Reference
Re inert and Severn,
Stauffer, 1982a
Stauffer, 1982a and
Jensen, 1982
Jensen, 1982
mg (1)

Yearly
Dermal Inhalation
1440
1870
8

580
1700
2980
2900
430
2980
2900
2200


1985

Re inert


4
5
0.008

1
4
7
7
1
7
7
5




and Severn, 1985



-------
                             11-63

     The most extensive exposure data base the Agency has is
for the application of pesticides to orchards using high pressure
or airblast equipment.  This data base was used to estimate
captan exposure to applicators, rather than the two studies
which have been conducted with captan (Stauffer, 1982; and
Deer, 1981).  While the exposures shown in the Stauffer and
Deer studies were in the same range as the Agency's data base,
the Agency believes that its data base is more scientifically
reliable.  Mixer/loader data from the Stauffer study were used,
however, because the Agency does not possess an extensive
generic data base on mixer/loaders.

     The orchard airblast data base consists of 23 nonproprietary
studies containing more than 1,000 exposure replicates.  A
linear regression analysis of dermal exposure as a function of
application rate revealed a valid predictive correlation which
was statistically significant at the <0.01 level.  The linear
regression lines fit the equation y = 4.8 x + 16, where "y" is
the dermal exposure in mg/hr (normalized to 3,000 cm2 of exposed
skin, i.e. long pants, short-sleeved shirt, no hat or gloves)
and "x" is the application rate in Ib. a.i./acre.  From this
data base, dermal exposure to applicators (assuming 2 Ib a.i./acre)
would be 26 mg/hr.

     Inhalation exposure for airblast applicators does not
correlate well with application rate.  For the 23 studies, the
mean inhalation exposure was 0.06 mg/hr (Day, 1982).

     For mixer/loaders, the Stauffer study showed dermal and
respiratory exposure of 180 and 6 mg/hr, respectively.

     The Agency used the following assumptions to estimate
worker exposure:

     1.  The worker does not wear special protective clothing
         such as a hat or gloves.  The  worker wears a short-
         sleeved, open-neck shirt, and long pants.

     2.  For a typical case there are 2 to 12 spray operations,
         with each operation lasting approximately 6 hours.

     3.  The mixing/loading operation takes 0.5 hours.

       (2) VEGETABLE CROPS AND ORNAMENTALS - FOLIAGE AND

                        PRE-HARVEST USES

     Generally vegetable and ornamental crops are treated with
captan using a tractor-mounted row-crop low-boom sprayer.
Growers with smaller acreages might use hand-held applicators.
A 50% WP is used most often at a rate of 2 to 5 pounds a.i.
per acre.

-------
                             11-64

     Because no captan row-crop exposure study was available to
the Agency, surrogate data were used.

     The data base used to assess dermal exposure for ground
boom applicators was on the results of a series of studies
sponsored by the Agency and carried out at various state
universities under the National Pesticide Hazard Assessment
Program.  The full report of these studies is currently undergoing
formal Agency Peer Review, but a summary of the studies has
been published (Reinert and Severn, 1985).

     The Agency used the Stauffer airblast study to assess
inhalation exposure for applicators and mixer/loaders and dermal
exposure for mixer/loaders.

     For dermal exposure, the Agency estimates 180 mg/hr for
mixer/loaders (Stauffer, 1982a) and 24 mg/hr for applicators
(Reinert and Severn, 1985).

     For respiratory exposure, the Agency estimates 6 mg/hr
for mixer/loaders and to 0.06 mg/hr for applicators (Stauffer,
1982).

     The Agency used the following assumptions to estimate
worker exposure:

     1.  The worker does not wear special protective clothing
         such as a hat or gloves.  The worker wears a short-
         sleeved, open-necked shirt, and long pants.

     2.  There are 4 to 20 applications per year.  Each application
         lasts an average of 6 hours.  This is a worst-case
         estimate.

     3.  The mixing/loading operation takes 0.5 hours.

       (3) HOME GARDENS - FOLIAGE AND PRE-HARVEST USES

     For home garden use, 90 percent of captan is applied to
fruit trees (Pelletier, 1982a). Other uses include vegetable
gardens, ornamental flowering plants, lawns, and dicondra ground
covers.  A variety of equipment (hose-end sprayers, atomizer
spray bottles, pump-up sprayers, dusters, etc.) is used.
Generally, a 50% WP is used at a rate of 0.8 oz a.i. in 5
gallons of water, although granular and captan WP formulations
with less active ingredient are available.

     The range of application exposure times depend on such
parameters as the crop treated, geographic location, size
of garden, and can widely vary.  No data are available for
estimating a reasonable minimum value.  However, as an estimate
for a home gardener using captan with a small vegetable garden,
the Agency assumes for a minimum value that the gardener will
take 20 minutes, twice a year.

-------
                             11-65

     The Agency used  the  following assumptions to estimate
worker exposure:

     1.  The home gardner does not wear special protective
         clothing such  as a hat or gloves.  A home gardener
         wears a short-sleeved, open-necked shirt, and long
         pants.

     2.  No published captan exposure studies were available.
         Although the Agency has several home gardener studies
         on surrogate chemicals, the use patterns for these
         studies were for application to low crops such as
         vegetable gardens and to ornamentals.  A model
         (Lavy et al. 1980) which represents the anticipated
         upper body exposure during fruit tree application more
         accurately was chosen.  In the study, the herbicide
         2,4,5-T (1.9%) was applied by backpack sprayer during
         typical forestry operations.  The average dermal and
         respiratory  exposures found were 26.7 and 0.027 mg/hr,
         respectively.  Corrected for concentration differences
         between captan (0.12%) and 2,4,5-T (1.9%), the equivalent
         captan values  would be 1.7 mg/hr dermal exposure and
         and 0.0017 mg/hr respiratory exposure.

     3.  The average  home gardener applying captan would have
         4 fruit trees.  The Agency estimates that it would
         take 1.25 hours  to mix and spray captan on these trees,
         and that 4 applications are made at least at seven-day
         intervals per  year (Pelletier, 1982a).

     Assuming 1.7 mg/hr exposure to captan for 1.2 hr/application,
a reasonable estimate of  the dermal exposure would be 2.0 mg/day
(or 8 mg/yr).

     For the respiratory exposure, a reasonable estimate of the
exposure to captan would be 0.002 mg/day (or 0.008 mg/year).

                    (4) NUT CROPS (ALMONDS)

     Captan is applied primarily as a 50% WP using ground
air-blast equipment,  however, aerial equipment may be used in
emergency situations  when extended periods of rain prevent use
of ground equipment.  Since data for captan exposure using
aerial equipment were not available, surrogate data were used
to estimate worker exposure.  An 80% captan WP formulation is
commonly used for aerial applications, at a rate of from 2.5 to
6 Ibs a.i. per 15 to  30 gallons of water.

     The Agency estimates that an average almond orchard is
52 acres, and that it would take up to 3 tankfuls per application
day to cover such a farm.  However, aerial application is
usually done by commercial applicators who would be applying
captan to more than one farm.   Because the almond orchards
are in a rather concentrated geographic area and aerial appli-

-------
                             11-66

cations are done during emergency situations, the timing of
application is critical.  Therefore,  it  is estimated that an
aerial application crew would be working  for a two-day period
for  3 applications, at 7 to 10 day  intervals.

     It is standard procedure that  the chemical  is pumped via  a
closed system into the spray tanks  after  mixing.

     The Agency used the following  assumptions to estimate exposure
for  mixer/loaders and pilots:

     1.  A mixer/loader and pilot wear a  short-sleeved, open-necked
         shirt, and long pants.

     2.  For estimating exposure to aerial mixer/loaders, no
         captan study was available to the Agency.  A surrogate
         study (Everhart and Holt,  1982)  using Benlate® (50%
         benomyl WP) during the mixing/loading was available.
         In this study, the average dermal and respiratory
         exposures were 1 mg and 0.004 mg, respectively, per
         pound of active ingredient loaded.  Five hundred Ibs.
         of Benlate® were assumed loaded  per application day.

     3   The Agency assumes that once a year a mixer/loader
         loads 800 Ibs. of captan per day for a  two-day period.

     4.  For evaluating exposure to pilots, a pilot would be
         exposed for 4 hours each day, for a two-day application
         period.  It is assumed, based on estimates made for
         pilots spraying EBDC's, that pilots are exposed dermally
         to 2.27 mg/hr (Jensen, 1982).  No significant respiratory
         exposure was found.

     For the mixer/loaders, the Agency estimates a daily dermal
exposure of 800 mg/day (or 1600 mg/year)  and a respiratory
exposure of 3.2 mg/day (or 6.4 mg/year).  The range is based on
the  use from one to 3 applications per year.   Therefore, the
high end of the annual exposure range is  three times these
dermal and respiratory exposure values.  One application lasting
two  days is considered the minimum of the range.   These values
represent exposure potential when no special protective clothing
is worn.

     For the pilots not involved with any mixing/loading tasks,
the Agency estimates a daily dermal exposure of  9 mg/day (or
18 mg/year) and negligible respiratory exposure.

               (5) APPLES - POST-HARVEST USES

     Captan is used mostly in the Northeast U.S.  as a post-
harvest treatment to prevent apples from  rotting during storage.
After harvest, apples contained in wooden bins are mechanically
dipped or sprayed with 0.1% captan suspension.   In the case of
the spray treatment method, the excess captan is recycled.

-------
                             11-67

After treatment, the apples are stored or sorted, washed,
waxed, and dried prior to shipment.

     Two workers per storage/packing house could potentially be
exposed to captan.  One may mix and control the captan suspension,
and one may oversee the apples being conveyed into and out of
the dip or drench area.  Spraying or dipping operations are
automated.  The worker who prepares the captan suspension, how-
ever, is the one with the potential for significant exposure to
captan.  Because of captan1s low vapor pressure and rapid hydrolysis
rate, volatilization of captan from the diptank suspension is
considered negligible.

     A worker in this situation would likely be wearing a
long-sleeved shirt and perhaps a hat because of the prevailing
autumn weather conditions; therefore, for this analysis,  only
hand exposure was considered.

     It is estimated that treatment periods range from 6  weeks
in West Virginia (with a mixer working 5 minutes per day  preparing
one batch of dip or spray suspension) to 12 weeks in Washington
State (with a mixer working 20 minutes per day preparing  the
captan suspensions and adding captan to the tanks when the
volumes of suspension are reduced) (Pelletier, 1982a).

     The Agency made the following assumptions to estimate
exposure:

     1.  A worker wears a long-sleeved shirt and long pants,
         but no gloves while mixing and maintaining the captan
         suspension for dipping and spraying.

     2.  No specific captan exposure model for this use was
         available to the Agency.  It is the Agency's judgment,
         however, that the exposure to the mixer for this post-
         harvest use would be similar to the exposure found
         during the mixing portion of the apple pre-harvest
         exposure study  (Stauffer, 1982a).  In this study, the
         mixer/loader was exposed dermally to 153 mg/hr on the
         hands and 28 mg/hr on the remainder of the exposed
         skin area.  Respiratory exposure was 5.9 mg/hr,  assuming
         a 1.2 m^/hr breathing rate.

     3.  A typical case as in West Virginia results in
         15 minutes mixing per day (3 batches) over a
         six-week period, or a total of 7.5 hours per year of
         exposure.

     For the worker who mixes the captan suspensions for this
post-harvest use, the Agency estimates a dermal exposure of
38.3 mg/day (or 1100 per year) and a respiratory exposure of
1.5 mg/day (or 45 mg/year).

-------
                             11-68

     For the range, a minimum value is derived from a 5 minute
per day mixing period for 6 weeks (2.5 hours total), which
would be reasonable for West Virginia.  A maximum value is
derived from the practice in Washington State, where mixing
times would likely be 20 minutes per day over an 8-month period
(53 hours total exposure).  The range of dermal exposure,
would be from 13 mg/day (or 390 mg/year) to 51 mg/day
(or 8,200 mg/yr).  The respiratory exposures would likely
range from 0.5 mg/day (or 15 mg/year) to 2 mg/day (or 320
mg/year).

         (6) POTATOES - PLANTING STOCK TREATMENT USES

     In the early spring seed potatoes are generally
cut by a potato-cutting machine (usually located indoors).  The
cut surfaces of the potato seed pieces are then dusted with
captan by means of a duster mounted on a conveyer belt.  The
captan treated potato seed pieces are then distributed by a movable
conveyer belt into the hoppers of a tractor-driver planter.

     Four dust formulations (ranging in concentration from 5 to
22.5% percent a.i.) and a 50% WP are registered for treatment
of potato seed pieces at a rate of 0.5 Ib a.i. per 100 Ib of
potato seed pieces.

     There is a wide variety of application practices for this
use.  In Maine, the average farm is about 90 acres.   Sufficient
seed pieces for one day's planting are treated with captan on
the planting day.  Two workers are involved in the treatment
operation.  One fills captan into the treater and oversees the
mechanical cutting operation. The other unloads and loads seed
material before and after treatment.  The Agency estimates the
exposure time would be 2.2 hrs for filling, 44 hrs for cutting,
and 45 hrs for planting (Pelletier, 1982a).  One worker would
also plant the seed material and the other would haul treated
seed fertilizer, and load the planter boxes.

     In Idaho, the farms are an estimated 300 acres.  Four to
5 workers are involved in the seed treatment operation.  The
operation is carried out for an eight-hour day over a 2 to 3
week period.  Assuming a 3 week exposure period, the exposure
times would be 7.2 hrs for filling, 44 hrs for cutting, and 45
hrs for planting.

     Potato planting usually takes place in areas of the northern
United States in the early spring, which is normally quite cool.
Workers are nearly always fully clothed with head coverings
and long-sleeved shirts or jackets.  For this reason, no potential
dermal exposure is estimated in this analysis for areas other
than the face, neck, and hands.

     The Agency used the following assumptions to estimate
worker exposure:

-------
                             11-69

         The potential dermal and respiratory exposures reported
         in the study by E. R. Stevens and J. E. Davis are
         representative of potato seed piece treatment across
         the U.S.  (Stevens and Davis, 1980).  A 5% captan
         dust formulation was used. The potential exposures
         varied considerably with work task and is summarized
         in Table  12.

         The use practices and exposure durations described
         for Maine are typical for most of the U.S., and the
         practices in Idaho represent the upper end of the
         range of  exposures for potato seed piece treatment.

         Only the  hands, face, and neck are not covered by
         protective clothing.

         In Maine, the total seed piece treatment/planting
         operation is estimated to take 5 consecutive days, once
         a year.   Broken down on a daily basis involving two
         people, person number one needs 0.44 hrs for filling
         and 8.8 hrs for cutting; and person number two needs
         5.6 hrs for planting.

         Because exposure estimates vary with the task involved,
         the Agency assumes that one person does the filling
         and cutting, and the other does the planting.
Table 12 — Potential Exposure of Workers to Captan During
Potato Seed Piece

Operation
Filling Duster
Cutting/Sorting

Average Dermal
Exposure not
including
handsl/
(mg/hr)
4.12
0.55
Treatment

Average
Hand
Exposure
(mg/hr)
3.56
N/A2

Average
Dermal
Exposure
(mg/hr)
7.68
0.55

Average
Respiratory
Exposure
(mg/hr)
0.82
0.04
Pieces
Planting Pieces   0.33
0.02
0.35
0.03
  I/Because potato seed piece treatment is done in early spring,
   which is usually quite cool, workers were clothed with head
   coverings and long-sleeved shirts or jackets.  Therefore,
   dermal exposure is estimated only for face, neck, and hands.

  2/Hand exposure is not included in the data because workers on
   the cutting machine always wore rubber gloves.

-------
                             11-70

     For a person doing the filling and cutting, the daily dermal
and respiratory exposures are estimated to be 8.2 mg/day (for
example, 0.44 hrs x 7.68 mg/hr + 8.8 hrs x 0.55 mg/hr) and 0.7
mg/day, respectively.  For the person doing the planting, the
dermal and respiratory exposures are estimated to be 2.0 mg/day
and 0.2 mg/day, respectively.  This exposure level would be
maintained for 5 consecutive days, once a year.

     The minimum end of the actual use range can be estimated
based on a small potato farm of approximately 10 acres.  Although
the daily exposures would likely be the same (i.e., 8.2 and
0.7 mg/day for dermal and respiratory exposures, respectively),
it is estimated that workers would be exposed for no more than
2 consecutive days per year.

     The maximum end of the range for this use can be found by
extending these exposures to fifteen consecutive days. This
would be applicable in Idaho, where farmers have larger acreages
available for planting with potatoes.  The daily exposures
for a person doing the cutting and filling would be still be
8.2 mg/day and 0.7 mg/day for dermal and respiratory, respectively,
but extending for 15 consecutive days per year.

       (7) SOYBEANS - PLANTER BOX SEED TREATMENT USES

     Seed can be treated in large, bulk seed quantities by
commercial seed companies; in smaller bulk quantities on the
farm before planting; or in planter boxes at the time of
planting.  The planter box method is most common because of its
convenience, and because it preserves the farmers'  options of
diverting untreated seed for use as animal feed.

     There are 2 types of planter box treatments.  The first
is called the mechanized planter box method.  A simple powder
metering device is located at the intake of the auger used to
transfer the seed from a bulk source to the planter.  The
second method, the one used for this analysis,  is the so-called
manual planter box method.  With this method, captan plus other
fungicides and/or insecticides are added by means of a container
or scoop to the seeds already in the planter box, then mixed
manually or by gravity/filtration.

     Captan is used as a seed treatment on many different types
of seed. It is reported that 96% of the corn seed treatments are
accomplished commercially and the remainder are treated by
individual growers (Pelletier, 1982a).  Soybeans, however, were
chosen as the representative crop for this analysis because a
large percentage of the soybeans treated with captan are treated
by using the manual planter box method.  The Agency assumes
this treatment practice has higher potential for applicator/
farmer exposure than the commercial practice.

     Commercially treated seed and seed augered  into hoppers
produce some  (albeit less) dust exposure than by the manual

-------
                             11-71

planter box method (Zoecon's Lindane PD 2/3 Rebuttal Submission,
1980.)

     Captan is formulated by itself or as a mixture with other
pesticides (such as diazinon, lindane, maneb, and methoxychlor)
to prevent a number of soil and seed borne diseases. Twenty-five
percent dusts are most commonly used, although dusts from 6%
to 75% are available.

     The average number of acres being planted with captan-treated
soybean seeds ranges from 29 to 100 (Pelletier, 1982a).  It is
estimated to take less than 1/4 hour for treating 4and loading
seed per 10 hour work day, with approximately 90 acres treated
in that time period (Zoecon's Lindane PD 2/3 Rebuttal Submission,
1980).  For estimating the range of exposures, the minimum was
based on a single exposure day (which would be reasonable for a
small soybean farm) and the maximum based on 3 days of exposure
(which would be reasonable for a large soybean farm).  Both
values assume a 0.25 hr/day for seed treatment and hopper
filling, and 7 hrs/day for seed planting.

     The Agency used the following assumptions to estimate
exposure:

     1.  A 25% dust formulation is used.

     2.  Since no actual captan planter box exposure study was
         available to the Agency, it is reasonable to use the
         exposure values found in the captan potato seed piece
         study (Stevens and Davis, 1980).  For a 5% dust formulation,
         the average dermal and respiratory values found while
         filling the duster were 7.68 and 0.82 mg/hr, respectively.
         Corrected for the use of a 25% dust formulation,
         exposure values of 38 and 4 mg/hr will be used for
         the combined operations of seed treatment and hopper
         fill.

     3.  No protective clothing was assumed.  A farmer treating
         seed using captan using the manual planter box method
         is assumed to be wearing a short-sleeved, open-necked shirt,
         long pants, no gloves or hat.

     4.  Seed treatment and hopper fill take 0.25 hours per day,
         2 days per year.  Seed sowing takes two 7-hour days,
         or 14 hours per year (Zoecon's Lindane PD 2/3 Rebuttal
         Response, 1980; Pelletier, 1982a).

     5.  Compared to seed treatment and hopper fill, the Agency
         assumes that the exposures are negligible for the
         actual seed planting operation.

     For seed treatment and hopper fill (the same person would
likely do both operations)/  the dermal and respiratory exposures

-------
                             11-72

are estimated to be 9.5 mg/day  (or 19 mg/year) and 1 mg/day
(or 2 mg/year), respectively.

     For seed treatment the dermal and respiratory exposures
are assumed to be negligible compared to the exposures while
treating seed and filling the hopper.

           2)  Harvesters (Fieldworkers)

     There are 7 available studies of fieldworker exposure to
captan applied to strawberries.  See Table 13 for detail of
the data from these studies and calculations of yearly exposure
(Adams, 1984).

     One of the studies was performed in Oregon where school-age
children are usually employed as pickers for about six weeks per
season with 30 days of exposure per year (Popendorf, 1984).
The children may only work for one season or less, and rarely
work in the strawberry harvest for more than 3 years.  The
strawberry picker exposure rate of 4.70 mg/hr for the Oregon
study was the lowest rate in the 7 studies.  Estimated lifetime
captan exposure derived from this study is 3.39 grams for
strawberry pickers in Oregon.

     Six of the studies were performed in California where
harvesting is usually done by residents of the area, and the
harvest may last for 80 work-days.  In this case, people may
work in strawberry agriculture for as many as 20 years (Popendorf,
1984).  One of these studies included exposure to weeders as
well as pickers.  In that case, exposure to weeders, at 94.13 mg/hr,
was much higher than to pickers, at 17.41 mg/hr.  However, the
weeding of strawberries is performed only about 10 days/season.

     The 6 California picker-exposure values range from 3.76 to
24.97 g/yr with a mean of 9.85 g/hr.  Based on the mean of
these measured values, lifetime exposure (20 years) for a
person only picking strawberries would be 197.0 g/lifetime.
The exposure for a California worker only engaged in weeding
strawberries, would be 150.6 g/lifetime.  Combination of the 2
tasks (10 days of weeding and 70 days of picking per year)
could lead to the largest lifetime exposure, [(9.85 g/yr)
(70/80) + 7.53 g/yr]  (20)  = 323.0 g/lifetime.

     Strawberry pickers and perhaps weeders have the opportunity
to eat the fruit.  That fruit is reported to average 0.62 ppm
(SD = 0.052) from 7 sets of residue data, whose means range
from undetectable to 1.20 ppm (Popendorf et al. 1982).  Assuming
that the workers eat a daily average of 430 g [(1 pint) (454
g/pint) (0.95 g/g density) = 430 g], a worker would ingest
0.00052 g/day [(430 g) (1.2 x 10-° g/g) = 0.00052 g/day]  of
captan residues with the fruit.  Addition of this ingestion
exposure to the exposures above increases the estimated lifetime
exposures.  The estimated lifetime exposures are: 3.44 g for
Oregon Pickers (0.00052 g/d)  (30 d/yr) (3 yr) + 3.39 g];  197.3

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                                     11-73
     Table 13 - Estimation of Fieldworker Exposure to Captan on Strawberries
Study
No.
1.
2.
3.
ii
4.
5.
6.
7.
State
Calif
Oreg
Calif
Calif
Calif
Calif
Calif
Calif
Task
Picking
Picking
Picking
Weeding
Picking
Picking
Picking
Picking
Days after
application
10
26
3
3
3
48
4
3
Non-ingestion
Exposure
mg/hr
6.50
4.70
17.41
94.13
16.37
5.88
39.01
7.15*
hr/d
8
8
8
8
8
8
8
1 8
d/yr
80
30
80
10
80
80
80
80
g/yr
4.16
1.13
11.14
7.53
10.48
3.76
24.97
4.58
References
Popendorf et al. 1982
Popendorf et al. 1982
Popendorf et al. 1982
Popendorf et al. 1982
Popendorf et al. 1982
Popendorf et al. 1982
Zweig et al. 1983
Winterlin et al. 1984
Mean for 6 Calif, picking studies:  15.38  mg/hr;    9.85 g/yr



* This has been corrected to include hand exposure.

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                             11-74

g  for California Pickers  (0.00052 g/d)  (80 d/yr)  (20 yr) +
197.4 g];  151.4 g for California Weeders  (0.00052 g/d)  (80
d/yr) (20  yr) + 150.6 g]; and 323.8 g for a combination of
picking  and weeding  in California  [(0.00052 g/d)  (80 d/yr)  (20
yr) + 323.0].  Ingestion  exposure relative to total exposure is
small, ranging from  1.4%  in Oregon to 0.3% for combined picking
and weeding in California.  However, that exposure portion may
be absorbed better than the dermal exposure.

            3) Cut Flower Production

     Captan is registered for use in controlling diseases in
cut flower production.  These flowers include carnations,
chrysanthemums, snapdragons, etc.  The use of captan on
chrysanthemums was selected as being typical of flower production
and use  practices.

     The Agency has  made  the following' assumptions about use
(Day, 1985, and Pelletier, 1985):

     1)  An average  acreage of flower production is eight acres.

     2)  Continuous, but  staggered production throughout the
         year such that there are 52 plantings per year.

     3)  Plants flower 3-5 months after planting.

     4)  Each plant  covers a 36 square inch area.

     5)  Captan is applied at the early bloom stage for a six
         month period during the year.

     Based on the above assumptions, spray treatment was
calculated to be 27  minutes/week for six months.  Total time
spent cutting stems  and boxing flowers would be 2.8 hours for
20-24 days over a six month period.  This is summarized as
follows:
Operation
Mix/load/cleanup
Spraying
Cutting/packing
Hours/Day
0.25
0.5
2.8
Days/Year
26
26
132
Hours/Year
6.5
13
370
     The Agency estimates that the respiratory exposure for
applicators and mixing and loading is 0.2 mg/hour and that the
dermal exposure for these activities is 17.0 mg/hour (Jensen, 1982)
For cutting and packaging of flowers, the Agency used surrogate
data from a study on malathion by Wolfe et al. (1967) to estimate
exposure:  the dermal exposure was 3.9 mg/hour for the first
day and 2.1 mg/hour two days after application.  The respiratory
exposure was essentially negligible (Day, 1985).   The exposure

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                             11-75

estimate for workers (70 kg) engaged in these activities is as
follows:

                                                 Exposure in mg
                       Exposure Rate mg/hr     Dermal      Inhalation
Operations    Hrs/Day  Dermal   Inhalation  Daily  Yearly  Daily  Yearly

Mix/load/      0.75      17         0.2      13     332     0.15    3.9
spray/cleanup

Cutting/       2.8        2         neg.      6     740     neg.    neg.
packaging

     Thus, based on a 70 kg person with no protective clothing, the
exposure to captan from the cut flower industry would be:

                           Exposure - mg/kg
                       Dermal           Inhalation
Operations	Daily  Yearly	Daily  Yearly

Mix/load/spray/      0.19    4.7       0.002    0.06
cleanup

Cutting/packaging    0.09   11         neg.     neg.


           4) Dietary Exposure - Oncogenic Risk

     To estimate dietary exposure of the U.S. population to
captan, the Agency assumed food residues were at tolerance
levels  (theoretical maximum residue contribution or TMRC), a
body weight of 60 kg, 100 percent of a crop is treated, and
standard food factors (i.e., percent of a crop in the diet).
These estimates represent the worst case dietary exposure
because residues are assumed to be at the highest levels which
are legally permissible on a crop.  Although actual residues
could be lower, adequate data were not available to allow such
a determination.  Table 14 summarizes these estimates.

     Data on pesticide residues found in food in the market
place were also evaluated.  The following surveys provided this
information.

      (a)  Stauffer Chemical Company Market Basket Surveys (fruits
           and processed fruit commodities only);

      (b)  Chevron Chemical Company Market Basket Surveys (fruits
           and processed fruit commodities only);

      (c)  Canadian residue data on imported commodities (fruits
           and vegetables); and

      (d)   FDA monitoring  programs for 1978-1981  (fruits and
           vegetables).

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                           11-76




Table 14 - Dietary "Worst Case" Exposure Based on Tolerances

Food Commodity or
Commodity Grouping
Almonds
Apples
Apricots
Avocados
Beans
Beet Greens
Beets
Blackberries
Blueberries
Broccoli
Brussels sprouts
Cabbage, sauerkraut
Cantalopes
Carrots
Cattle
Cauliflower
Celery
Cherries
Collards
Corn, sweet
Cottonseed
Crabapples
Cranberries
Cucumbers, pickles
Dewberries
Eggplant
Garlic
Grapefruit
Grapes, raisins
Hogs
Honeydew melons
Kale
Leeks
Lemons
Lettuce
Limes
Mangoes
Muskmelons
Mustard Greens
for

Food Factor
(percent diet)
0.03
2.53
0.11
0.03
2.04
0.03
0.17
0.03
0.03
0.10
0.03
0.74
0.52
0.48
7.18
0.07
0.29
0.10
0.08
1.43
0.15
0.03
0.03
0.73
0.03
0.03
0.03
0.99
0.49
3.43
0.03
0.03
0.03
0.17
1.31
0.17
0.03
0.03
0,06
Captan

Tolerance
(ppn)
2.00
25.00
50.00
25.00
25.00
100.00
2.00
25.00
25.00
2.00
2.00
2.00
25.00
2.00
0.05
2.00
50.00
100.00
2.00
2.00
2.00
25.00
25.00
25.00
25.00
25.00
25.00
25.00
50.00
0.05
25.00
2.00
50.00
25.00
100.00
25.00
50.00
25.00
2.00

Daily Intake
(mg/1.5kg
diet/day)
0.00090
0.94875
0.08431
0.01125
0.36500
0.04500
0.00521
0.01125
0.01125
0.00307
0.00090
0.02207
0.19545
0.01441
0.00539
0.00215
0.21461
0.15330
0.00246
0.04290
0.00450
0.01125
0.01125
0.27210
0.01125
0.01125
0.01125
0.37174
0.36791
0.00258
0.01125
0.00090
0.02250
0.06515
1.96219
0.06515
0.02250
0.01125
0.00184

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Table 14 (continued)
                                            11-77
Food Conmodity or
Commodity Grouping
Nectarines
Onions (dry bulbs)
Onions, green
Oranges
Peaches
Pears
Peas
Peppers
Pimentos
Pineapple
Plums, Prunes
Potatoes
Pumpkin, Squash
Quinces
Raspberries
Rhubarb
Rutabagas
Shallots
Soybeans (oil)
Spinach
Strawberries
Summer Squash
Tangerines
Taro
Tomatoes
Winter Squash
Food Factor
(percent diet)
0.03
0.72
0.11
2.17
0.90
0.26
0.69
0.12
0.03
0.30
0.13
5.43
0.11
0.03
0.03
0.05
0.03
0.03
0.92
0.05
0.18
0.03
0.03
0.03
2.87
0.03
Tolerance
(ppm)
50.00
25.00
50.00
25.00
50.00
25.00
2.00
25.00
25.00
25.00
50.00
25.00
25.00
25.00
25.00
25.00
2.00
50.00
2.00
100.00
25.00
25.00
25.00
0.250
25.00
25.00
Daily Intake
(mg/1.5kg
diet/day)
0.02250
0.26827
0.08431
0.81247
1.34900
0.09581
0.02085
0.04599
0.01125
0.11114
0.19928
2.03500
0.04216
0.01125
0.01125
0.01916
0.00090
0.02250
0.02754
0.07665
0.06898
0.01125
0.01125
0.00011
1.07805
0.01125

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                             11-78

     However, the survey data that were submitted were not
reliable enough to assess dietary exposure or to make a regulatory
decision for the following reasons:

     a)  There may be a mixture of treated and untreated food
in the survey, resulting in observed residues which are lower
than tolerances.

     b)  There was no indication on the frequency of application
or the amount of captan applied to the crops.

     For informational purposes, exposure estimates using this
information are presented in Table 15.

     The seed treatment use of captan is now considered a food
use.  Although the Agency does not have data for residues in
plants which might result from seed treatment, it is assuming,
for the present, that the resulting residues would be at or
below the limit of detection, and that based on those levels the
dietary risks to humans would be insignificant.  The Agency
will be requesting residue data for seed treatments.

     There are tolerances for detreated corn seed that is fed
to cattle and hogs.  This seed was previously treated with
captan, but because it was not planted, the left over treated
seed is detreated to remove captan from the seed.  Based on
feeding studies submitted by Chevron that showed that there
would be no likely captan residues in these animals if a pre-
slaughter interval of 14 days were adopted, no human dietary
exposure is expected.  A tolerance of 100 ppm was set (21 CFR
561.65).

           5) Dietary Exposure - Teratogenic Risk

     To estimate dietary exposure to captan for use in the
teratogenic risk assessment, the Agency also used the tolerances
and 60 kg average body weight.  However, food factors were not
used.  Since one dose could cause an acute, teratogenic effect
(as opposed to multiple doses causing a chronic, oncogenic
effect), the Agency used "single serving" values (USDA, 1977).
Table 16 summarizes the results.

        b.   Non-Agricultural Uses

     The Agency has reviewed information related to some of the
minor non-agricultural uses of captan (Day, 1984b).  Captan is
used in plastics, wallpaper flour adhesive, paints, cosmetics

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                             11-79
      Table 15 - Captan Dietary Exposure Based on Surveys
Food Commodity
or Grouping
Almonds
Apples
Fresh
Canned
Juice
Apricots
Blackberries
Blueberries
Cherries
(incl. canned)
Grapes
Fresh
Juice
Raisins
Lettuce
Nectarines
Oranges
Fresh
Frozen
Juice
Peaches
Fresh/Frozen
Canned
Pears
(incl. canned)
Plums, Prunes
Raspberries
Strawberries
Fresh
Frozen/Jam
Food
Factor
(% diet)
0.03

2.00
0.32
0.21
0.11
0.03
0.03
0.10


0.30
0.15
0.04
1.31
0.03

1.35
0.40
0.42

0.42
0.48
0.26

0.13
0.03

0.15
0.03
Average
of Actual
Residues
(ppm)
0.003

0.08
0.007
0.007
1.041
0.078
0.062
0.39


0.74
0.006
0.011
0.09
0.053

0.000
0.017
0.0115

1.00
0.017
0.03

0.012
1.355

1.67
0.071
Daily Intake
(ug/1.5 kg
diet/day)
0.0014

2.4000
0.0336
0.0347
1.17177
0.0351
0.0279
0.585


3.3300
0.0135
0.0066
1.7685
0.0239

0.0000
0.1020
0.0-/25

6.3000
0.1224
0.1287

0.0234
0.6098

3.7575
0.0320
Tomatoes
2.87
0.07
3.0135

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                             11-80




Table 16 - Captan Dietary "Single Serving"  Exposure Estimate

Food Commodity or Single Servingl/ Tolerance
Grouping
Almonds
Apples
Apricots
Avocados
Beans, Lima, fresh
Bean, Snap, fresh
Beet Greens
Beets
Blackberries
Blueberries
Broccoli
Brussels sprouts
Cabbage, sauerkraut
Cantaloupes
Carrots
Cauliflower
Celery
Cherries
Collards
Corn, sweet
Cottonseed
Crabapples
Cranberries
Cucumbers, pickles
Dewberries
Eggplant
Garlic
Grapefruit
Grapes
Raisins
Honeydew Melons
Kale
Leeks
Lemons
Lettuce
Limes
Mangoes
Muskmelons
Mustard Greens
Nectarines
Onions (dry bulb)
Onions, green
Oranges, (juice)
Peaches
Pears
Peas (dried)
Peppers
Pimentos
(Kg)
Unknown
0.212
0.114
0.150
0.072
0.055
0.076
0.080
0.072
0.072
0.092
0.078
0.090
0.160
0.110
0.115
0.120
0.145
0.095
0.080
unknown
unknown
0.070
0.144
0.072
0.100
0.003
0.101
0-.080
0.145
0.170
0.055
unknown
0.016
0.057
0.016
0.082
0.160
0.070
0.150
0.171
0.025
0.245
0.152
0.180
0.200
0.100
0.018
(ppm)
2.00
25.00
50.00
25.00
25.00
25.00
100.00
2.00
25.00
25.00
25.00
2.00
2.00
25.00
2.00
2.00
50.00
100.00
2.00
2.00
2.00
25.00
25.00
25.00
25.00
25.00
25.00
25.00
50.00
50.00
25.00
2.00
50.00
25.00
100.00
25.00
50.00
25.00
2.00
50.00
25.00
50.00
25.00
50.00
25.00
2.00
25.00
25.00
Daily Intake
(mg/day)
_
5.30
5.70
' 3.75
1.80
1.38
7.60
0.16
1.80
1.80
0.18
0.16
0.18
4.00
0.22
0.23
3.00
14.50
0.19
0.16
-
-
1.75
3.60
1.80
2.50
0.08
2.50
4.00
7.25
4.25
0.11
—
0.40
5.70
0.40
4.10
4.00
0.14
7.50
4.28
1.25
6.12
7.60
4.50
0.40
2.50
0.45

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                             11-81
Table 16 - continued
Food Commodity or
Grouping
Pineapple
Plums, Prunes
Potatoes
Pumpkin
Quinces
Raspberries
Rhubarb
Rutabagas
Shallots
Soybeans (curd)
Spinach
Squash (winter)
Strawberries
Summer Squash
Tangerines
Taro
Tomatoes
Turnips
Turnip Greens
Watermelon
Single Serving!/
(Kg)
0.084
0.070
0.169
0.245
unknown
0.072
0.122
0.120
0.010
0.120
0.055
0.222
0.075
0.120
0.100
unknown
0.181
0.130
0.072
0.160
Tolerance
(ppm)
25.00
50.00
25.00
25.00
25.00
25.00
25.00
2.00
50.00
2.00
100.00
25.00
25.00
25.00
25.00
0.25
25.00
2.00
2.00
25.00
Daily Intake
(mg/day )
2.10
3.50
4.22
6.12
—
1.80
3.05
0.24
0.50
0.24
5.50
5.55
1.88
3.00
2.50
—
4.52
0.26
0.14
4.00
I/  Source: USDA, 1977

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                             11-82

and shampoos, surface sprays, pet powders, and packing crates
to prevent fungal attack.  These captan uses are somewhat
specialized in that they are used to prevent fungal deterioration
of organic substrates as opposed to use to prevent crop diseases.

     In these uses, potential human exposure falls into two
categories: (1) exposure to workers in adding captan formulations
to inert products and (2) exposure to users of these end-use
products treated with captan residues.  Because of the difficulty
in estimating exposure for specific uses for the formulations
and the products themselves, the Agency has addressed only
currently registered uses of captan and has made some general
assumptions on the potential exposure to users only for likely
exposure situations.

     The relevant use situations were obtained from a Mitre
Corporation Report  (Mitre, 1981).  This report is believed to
represent the latest information on these non-agricultural uses
of captan.

           1) Plastics

     Captan is used to inhibit fungal growth in plastic and
rubber products.  Though many of these polymers are inherently
resistant to fungal attack, the additives, such as plasticizers,
are not.  Captan is added to protect these degradable additives
and is particularly useful for the protection of products in
warm, humid environments.

                       Use as an Additive

     For these uses, EPA registered captan pesticide products
containing 45-90% a.i. are employed.  This powder formulation is
added to vinyl, rubber, and polyethylene products at 0.5-3% w/w
a.i.  This use of captan in 1979 was 75,000 Ibs.  The use of
captan has declined in recent years in favor of other products
with more thermal stability, less UV sensitivity, and less tendency
to discolor.

     The primary products manufactured from these vinyl, rubber
and polyethylene products containing captan as an additive are
mattress covers, car vinyl tops, rubber gaskets, and vinyl
coated fabrics.  One use, for swimming pool liners, was dis-
continued when it was found that captan leached into the water.
The current alternatives to captan are in general superior to
captan in many respects and it is suggested that more effective
and desirable alternatives exist.  Because the toxicity data
base for these chemicals is incomplete, some alternatives may
be more, less, or equal to captan in toxicity.  It is not
possible to compare the toxicity of the alternatives to captan
at the present time.

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                             11-83

     The Mitre report mentioned above describes a site visit to
the only plant currently employing captan to make laminated
vinyl fabric.  They use 90% a.i. captan which arrives in 50 Ib.
bags.  The bags are manually dumped into a mixer by a worker (2
bags per batch).  The worker wears rubber gloves, a respirator,
and a company supplied uniform.  The mixing area has an exhaust
fan to remove particles/dust and workers are required to wear
dust masks if they frequent the mixing area.  The adhesive mix
is then added to the laminator with an automatic pump.

                     Exposure  (Application)

     It appears from the description little exposure is incurred.
Ordinarily,  it would be improper to assume little exposure for
this application, but based on the controls and protective clothing
and since this is the only plant currently using captan (11,000
Ibs/year), the exposure for this particular use seems negligible.

                         Exposure (Use)

     There is extensive use of captan-containing bedding
(mattresses  and pillows); the use is primarily institutional
e.g. hospitals, nursing homes, etc.  The treated material is
often in skin contact with persons and in a possibly wet environ-
ment.  Untreated fabric rubbed across treated fabric imparts
the former with antimicrobial activity implying transfer of
captan from  the surface of the treated material.  For the
exposure estimation, the Agency assumed that in some situations
(e.g. psychiatric hospitals) there may be no covering over the
mattresses and pillows.  The dermal exposure, as calculated
below, is 6 mg/day (0.003 mg/kg/day).

                       Exposure Estimation

     In a previous exposure situation analagous to captan, vinyl
material was treated with OBPA (10, 10-Oxybisphenoxarsine).  This
compound has the same purpose and is used in vinyl materials.
Below is a comparision of their properties:

Property                    Captan         OBPA

% use concentration w/w      0.3            0.03

Vapor pressure mm Hg        1X10~5         1X10~6

Water solubility ppm        <0.5            10

Molecular Weight            301             502

                     Inhalation Exposure

     The Agency has no monitoring data to estimate the concentration
of captan in the air from use  in mattresses and pillows, but

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                             11-84

assumes the exposure  is negligible, because the concentration
is  low  (0.3%), the vapor pressure is low, and the captan  is
contained  in a vinyl  matrix.

                         Dermal Exposure

      In the OBPA exposure estimate, marine upholstery leached
at  a  rate  of 12.1 mg/m2/24 hour period.  Subsequent leaching
of  this material produced less than 50% of the amount.
Assuming OBPA and captan have similar leaching propensity,
but taking into account concentration and water solubility,
a worst case estimate of possible dermal exposure can be made.

12.1  mg/m2/day X 0.3  (cone, factor) X 0.5 (sol. factor) X
                 0.03                 10

1 m2  (half body area) = 6 mg/day (0.003 mg/kg/day)

      The Agency assumes that this would be significantly reduced
if  the mattresses and pillows were covered as is the normal practice
in  hospitals and nursing homes.

           2) Adhesives

      The use of captan in adhesives is primarily in the production
of  wallpaper flour adhesives.  Captan is used to prevent fungal
growth  in  the dry paste adhesive, later when water is added,
and as protection against fungi when paper is exposed to moisture
or  humid conditions.  Unprotected adhesive would, if moisture
is  present, be attacked by fungi and result in loss of integrity
of  the bonding.

                       Use as an Additive

      The only significant adhesive use of captan is in the
production of wallpaper adhesive paste.  This use consumes 5000
Ib  90% a.i.  product per year.  With the advent of resin based
adhesives which may not require water,  and the use of other
preservatives, captan use has decreased to such an extent that
its use is limited to one plant in Iowa which still utilizes
captan in making one type of wallpaper adhesive.

     The captan product (Vancide 89, 90% a.i.) is added to the
flour paste at the rate of 0.6% w/w.  The formulation arrives
in  50 pound drums and is weighed out 48 pounds at a time.  This
amount is used per 24 hour period.   This operation requires
about two minutes.

     Gloves and respirator are worn during the weighing operation.
The total amount is then added to an automatic feed device
(about 30 seconds;  no protective clothing)  and added to the
starch/water paste mixture and dried (300°F)  on rollers.  During
the 30 second period where no protective clothing is worn,
exposure to the hands is possible.  The Agency assumes the

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                             11-85

applicator will  be exposed  to  200 mg/day, covering the surfaces
of both hands  (Day,  1984b).  The dried product is subsequently
scraped off, ground  up,  and bagged for shipment.  A ventilation
hood  is located  over the  roll  dryers to carry away vapors.

                      Exposure  (Application)

      Although  the Mitre Report claims exposure is minimal,
there are several opportunities for exposure to workers.


Operation                        Exposure

Weighing                         Probably negligible
                                 due to protective clothing.

Addition                         Inhalation/dermal exposure

Drying                           Inhalation

Packaging                        Inhalation

General Work Area                Inhalation

                          Exposure (Use)

      The packaged wallpaper adhesive contains about 0.6% captan
and is widely  distributed for  use.  Workers who pour/measure
out the adhesive, and use it for glueing wallpaper could receive
some  exposure  during mixing and application.

           3)  Paints

      Captan is registered for  use as a biocide in paint
formulations.  They  fall  into  three areas:  in-container
preservative, mildewcide  for dry paint films, and antifoulants
for marine applications.  Annual consumption of captan in the
paint industry is estimated at 50,000 Ibs.  Less than 1% of the
paint manufacturers  (about  10) use captan.  There are many
alternative biocides available and in use.

                       Use  as  an Additive

     The paints  containing  captan are usually formulated for
special situations,  such as  breweries and sugar refineries,
where high humidity  promotes the growth of fungi.  Captan is
added to the level of 1% w/w.

     Only one plant  was identified in the survey as being an
active user of captan.  The  plant has manufactured a paint
designed for use in  sugar refineries for 15 years.  Vancide 89
(90%  a.i.  captan) is received  in 55 pound drums.  It is added to
the paint formulation at the mixing stage.  About 5-7 pounds of
Vanicide is weighed  out and  sifted into the formulation from a

-------
                             11-86

paper bag.  Application time is about one minute.  Gloves and
respirator are worn for this application.  The paint is then
canned and packaged for shipment.  Only about 10 batches of
this paint are produced yearly.

                     Exposure  (Application)

     The Mitre report claims an annual use of 50,000 Ibs; yet
the only paint plant found used only 100 Ibs. per year.  This
is a large discrepancy.  It could be that the larger total use
figure is outdated and other products are now being used instead.
Captan has the undesirable trait of causing a color shift in
paint over a period of time.

     For worker exposure, potential inhalation and dermal
exposure are likely to be mitigated by wearing gloves and a
respirator during the weighing and addition operation.  This
may not be true at other unidentified plants that manufacture
captan-containing paint.  No mention was made about cleanup
operations of the formulation areas which could result in exposure
if protective clothing is not used.

                        Exposure (User)

     The paint as received for use contains 1% captan.  A
painter using either a brush or sprayer could receive dermal
exposure from the paint (6 grams of paint/day 10 days/year).
This may be particularly significant because they are generally
oil base paints which may enhance dermal absorption.

           4) Cosmetics

     Captan is registered for use with the Food and Drug Admin-
istration (FDA) as an antimicrobial agent in cosmetic formulations
which include perfume, cosmetics, shampoo and shaving products.
The cosmetics containing captan are regulated by the FDA.

                       Use as an Additive

     Captan is used to prevent microbial growth in the cosmetic
formulations; also they inhibit growth of fungi/bacteria on the
skin.  Some dandruff shampoos incorporate captan as an active
ingredient.   Protection of the cosmetic is particularly important
in the case of oil-in-water emulsions.

     The only captan product registered with the EPA for form-
altion into a powdered hand soap is Vancide 89 which contains
87% captan.   To make the sanitizing deodorant powdered hand soap,
1% Vancide 89 is added by weight of the anhydrous soap.  (It is
also used in wallpaper paste and rubber coated articles.)  An-
other captan product,  PETRX, is registered with EPA for use as
a  dog or cat shampoo;  the insecticide in the product kills fleas
and lice while captan controls fungal growth on the animal's skin.

-------
                             11-87

     There are 36 cosmetic products registered with EPA and FDA
that contain captan.  Total usage of captan in these products
was estimated at 50,000 Ibs. in 1980,  Captan is added at the
rate of 0.1-0.2% w/w for simple aqueous solutions and 0.2-0.5%
w/w for creams and emulsions.  The use of captan as a preservative
is still important, but declining.  Many substitutes exist for
captan.

                     Exposure (Application)

     Captan is received in 20-25 kg drums and is weighed out by
one worker who wears a dust mask, gloves and disposable apron.
The operation requires about two minutes and is performed about
36 times per year.  After mixing there is no further direct
worker exposure.

                        Exposure (User)

     The cosmetic products listed in the Mitre report cover a
wide range of products:  shampoo for humans and animals, tooth-
paste, lotions, creams, etc.  Application results in both dermal
and oral exposure.  Many of these products can be characterized
as being absorbed completely by the skin; therefore the captan
present would also be carried into the skin at a rate approaching
100% (0.833 mg/kg/day).  These products are regulated by the
FDA, except for Vancide 89 and animal shampoos or dusts which
are regulated by EPA.

           5) Other Uses

     Captan is also incorporated in aerosol sprays, pet powders
and packing boxes.  Exposure from use of these products was
estimated by the Agency as follows (Reinert, 1985):

                         Surface Sprays

     Captan is added to spray formulations used for surface
treatment of awnings, clothing, drapes, rugs, etc. at 0.04% and
to spray formulations used on pets at 0.25%.  For a model to
estimate exposure from aerosol pet spray the study by Staiff
(1975) is the most appropriate surrogate.  In this study on
aerosol can use of paraquat (0.44%) in a yard/garden situation,
mean dermal exposure (15 samples-range 0.01 - 0.57 mg/hr) was
found to be 0.3 mg/hr.  Inhalation exposure was found to be
negligible.  The Agency assumes the surface sprays will be used
for 5 minutes once a week throughout the year.

                          Pet Powders

     Captan is incorporated in some pet powders at the level of
0.5% a.i.  The Agency assumes it will be used once a week
throughout the year and that a person applying pet powder will
be exposed to 200 mg per use (Day, 1985).

-------
                             11-88

                         Packing Boxes

     Captan is used as a supplement for wood preservative
treatment with inorganic arsenicals.  This process involves
pressure treatment and captan would be incorporated into the
wood and very little would be at the surface.  The Agency
assumes that that there would not be significant dermal or
inhalation exposure from captan in wood used to make packing
crates. Thus exposure from this use of captan is estimated to be
negligible.

     Exposure to humans from use of these end products is
summarized as follows:
                   Dermal Exposure Estimation^/

                                   Exposure (mg)
Exposure (mg/kg)
Use
Aerosol sprays^/
Pet powders^/
Packing boxes
Exposure
0.3 mg/hr
200 mg x (0.005)
Negligible
Daily
0.025
1.0
-
Yearly
1.3
52
-
Daily
0.00036
0.014
-
Yearly
0.019
0.74
-
I/  The Agency assumes that inhalation exposure is negligible for
    these three exposure situations.

2/  The Agency estimates that use is 52 times per year and that
    0.3 mg/hr is the mean dermal exposure.

3/  The concentration of captan in pet powders is 0.5% a.i.

           6) Summary of Assessment of Exposure from the
              Various Non-agricultural Uses of Captan

     For application of captan it is assumed that protective
clothing will eliminate significant exposure.  Estimates of
exposure for manufacturing and product use  are summarized in
Tables 17 and 18.  The adhesive use,  in particular is difficult
to quantify because of the heating of captan and the dust
formation after drying.  Others in the manufacturing plant may
be exposed, but no estimate can be made.

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                                  11-89
     Table 17 - Non-Agricultural Application Exposure Estimates
Cone.
Use AI%
Plastics
Adhesives
Paints
Cosmetics
90
90
90
90
Weigh/Applicat.
Exposure Period
Min.
Day
1
2.5
1
2
Min.
Year
250
180
10
36
Protect.
Clothing
yes
yes*
yes
yes
Total
Dermal
0
200
0
0
mg/day
Inhalation
0
10
0
0
mg
Yearly
0
7560
0
0
 but not during addition period of 0.5 min.  All exposure based on
 the 0.5 min. period.  (Mitre Corporation, 1981 and Day, 1984c)

        Table 18 - Exposure from Non-Agricultural Product Use (1)
Use
 Cone.        Exposure           Est. quantity   Dermal  Exposure
_w/w	Public	Professionals	of  product  (gm) mg/day  mg/year
Plastics   0.5-3

Adhesives  0.6

Paints (5) 1

Cosmetics

-animal
 shampoos(5)
          neg.

          yes

          neg.
neg.

yes

yes
neg.

6 (2)

6 (3)
neg,

36

60
  neg.

70, 3600 (2)

  600
           0.1-0.5 yes
                   NA
-Powdered
  soap(6)  0.87
         yes
                    NA
          10 (4)


            10 (4)
            50
      5000
              87
        9048
(1)  Inhalation exposure is negligible due to low vapor pressure.
(2)  Assumes contact with 6 gms of wet adhesive for 2 days/year for
     the public and 100 days/year for the professional user.
(3)  Assumes painter will contact 6 gms of paint/day 10 days/yr.
(4)  Assumes use of 10 gms lotion/shampoo products twice a week.
(5)  The human dermal absorption of these products is assumed to be
     100%.
(6)  The dermal absorption of these products in water is assumed
     to be 1.3% (Zendzian, 1982).
     (Mitre Corporation, 1981 and Day, 1984c)

-------
                            11-90

    4.  Risk Characterization

        a.  Dietary Risk (Food Residues)

     The captan dietary risk numbers were derived making the
following assumptions (Saito, 1984):

       0  Residues would be present on crops at tolerance
          levels, or at market-basket levels.

       0  EPA food factors (percent of commodity in
          diet) were used.

       0  A person eats 1.5 kg of food per day.

       0  A person weighs 60 kg.

       0  The Qj* for captan was 2.3 x 10~3 (mg/kg/day)-1

     A sample calculation for apples is provided:

mg of pesticide = tolerance x food factor x 1.5 kg diet

mg of pesticide = 25 mg x 0.0253 x 1.5 kg = 0.949 mg
                   kg

mg of pesticides  = 0.949 mg = 0.016 mg_
kg of body weight     60 kg          kg

Risk = Qjx exposure

Risk = 2.3 x 10~3 (mg/kg/day)-1 x 0.016 mg/kg/day

Risk = 10-4 (B2) to 10-5 (B2)

     Table 19 presents the dietary risks to the U.S. population
based, for comparison purposes, on published tolerances and
Market Basket Surveys.  The estimates represent the upper
limit of excess cancer risk which is not likely to be exceeded.

     Accurate data are not yet available on daily intake of
captan.  The best available data are 7.013 mg/1.5 kg diet/day
for a TMRC (Theoretical Maximum Residue Concentration) value
and .011 mg/1.5 kg diet/day for intake based on residues
from Market Basket Surveys (Jensen, 1982).

     These dietary estimates of intake divided by 60 kg
approximate the daily intake of captan as .1169 mg/kg (body
weight)/day and .00018 mg/kg/day based respectively on tolerances
and market basket residues.  When multiplied by Q±*, the
upper 95% bound on cancer risk are:

-------
                          11-91

                 10~3 (B2) to 10-4 (B2) based on tolerances
                 10-6 (B2) to 10~7 (B2) based on market
                                        basket surveys

                                           (Lacayo,  1984)

Table 19 - Estimate of Upper Bound Risk (95% Confidence Level)
           for Captan Associated with Diet Based on  Published
           Tolerances or Market Basket Surveys*/
Crop
Potatoes
Lettuce
Peaches
Tomatoes
Apples
Beans
Oranges
Grapes, including raisins
Grapefruit
Cucumbers, inc pickles
Onion (dry bulb)
Celery
Plums, including prunes
Cantaloupe
Cherries
Pineapple
Pears
Apricots
Onions, green
Spinach
Strawberries
Peppers
Lemons
Limes
Beet greens
Pumpkin, including squash
Corn, sweet
Soybeans (oil)
Leeks
Mangoes
Nectarines
Shallots
Cabbage, sauerkraut
Peas
Rhubarb
Carrots
Avocados
Blackberries
Blueberries
Crabapples
Cranberries
For Published
Tolerances
10~4
10-4 to 10-5
10-4 to 1Q-5
10-4 to 10-5
10-4 to 10-5
10-5
10-5
10-5
10-5
10-5
10-5
10-5
10-5
10-5 to 10-6
10-5 to 10-6
10-5 to 10-6
10-5 to 10-6
10-6
10-6
10-6
10-6
10-6
10-6
10-6
10-6
10-6
10-6
ID"6
^
10-6
10-6
10-6
10-6
10-6
10-6 to 10-7
10-6 to 10-7
10-6 to 10-7
10-6 to 10-7
10-6 to 10-7
10-6 to 10-7
10-6 to 10-7
For Market^/
Basket

10-7 to 10~8
10-7
10-7
10-7







10-9

10-8

10-8 to 10-9
10-7 to 10-8


10-7








10-9






10-9
10-8



-------
                            11-92
       Table 19 (continued)
Crop
Dewberries
Eggplant
Garlic
Honeydew melons
Muskmelons
Pimentos
Quinces
Raspberries
Summer Squash
Tangerines
Winter Squash
Beets
Cattle
Cottonseed (oil)
Broccoli
Hogs
Collards
Cauliflower
Mustard Greens
Brus ils Sprouts
Kale
Rutabagas
Almonds
Taro
For Published For Market^/
Tolerances Basket
10~b to 10- I
10-6 to 10-7
10-6 to 10-7
10-6 to 10-7
10-6 to 10-7
10-6 to 10-7
10-6 to 10-7
10-6 to 10-7
10-6 to 10-7
10-6 to 10-7
10-6 to 10-7
10-7
10-7
10-7
10-7
10-7
10-7
10-7 to 10-8
10-7 to 10-8
10-8
10-8
10-8
10-8
10-8 to 10~9







10-8














10-1° to 10--
1
I/ Captan is classified as a Probable Human Carcinogen (Group
   B2) in accordance with the Agency's Proposed Guidelines
   (U.S. EPA, 1984, 49 FR 46294).

2/ Based on Stauffer Chemical Company Market Basket Surveys (1979),
   Chevron Chemical Company Market Basket Survey (1978),  Canadian
   residue data (Stalker, 1981), FDA monitoring programs  for
   1978-1981 (Gunderson, 1982).

     The above values summarize the risks for all the individual
crops shown, taking into account the percentage of the particular
food in a person's diet each day.  The values do not take into
account the percent of the crop treated with captan.  The percent
crop treated was not used due to lack of marketing information
which shows that the treated crop would be distributed and
diluted nationally.  However, if such information were provided,
the Agency may be able to use the percent crop treated where
justified.

     Because tolerances indicate the residues which could
legally be present on crops, the Agency will base its proposed
regulatory action (agricultural uses) on the total dietary
risk of 10"3 (B2)  to 10~4 (B2) based on established tolerances.
The residues actually on the crops are probably not that
high, but the Agency has no other data on which to base a
regulatory decision for risk from dietary exposure to all
food crops in a person's diet.

-------
                            11-93

     Captan was registered for use on seeds without submission
of data to establish tolerances for the plants which grow
from the seeds and which, therefore, may contain residues of
captan and/or its metabolites.  Although the Agency does not have
data for residues in plants which might result from seed
treatment, it is assuming, for the present, that the resulting
residues would be at or below the limit of detection,  and
that dietary risks to humans would be insignificant.  The
Agency will be requesting such residue data.

     For detreated (washed) corn seed fed to animals,  the Agency
expects no residues to result in cattle or hogs as long as
treated corn seeds are detreated to reduce captan to the 100
ppm tolerance and as long as a 14-day pre-slaughter interval
is observed.  Thus, no residues are expected to result from
the use of detreated corn seed to feed cattle and hogs.  The
tolerance and pre-slaughter interval were based on feeding
studies submitted by Chevron.

        b.  Applicator and Mixer/Loader Risk

     To estimate dermal absorption and risk to applicators and
mixer/loaders, the following steps and/or assumptions were
used (Day, 1984a and Lacayo, 1984).

     1)  Calculate the agent arrival rate, r, in milligrams per
hour.  For example, if a worker is exposed to 100 mg/day of
Captan, then in a typical 8-hour work day, the arrival rate is
100/8 = 12.5 mg/hour.

     2)  Calculate the mg/day absorbed by the worker using
the formula:

                 Total Agent Absorbed = A (h,a,r)

                 = r [(h + 1) - (l/a)(l-(l-a)h + 1)]

                 where r = arrival rate of agent in milligrams
                           per hour.

                       h = total number of hours exposed (6 hrs).

                       a = absorption rate per hour of the
                           amount of agent present (1.3% per
                           hour from Zendzian, 1982 and
                           Lacayo, 1984).

                 then the worker dose in mg/kg/day is
                 A (h, a, r) /7 0.

     The dermal absorption of 1.3% per hour is based on a
study in rats submitted by Stauffer (1982b) and evaluated by
the Agency (Zendzian, 1982).  The Agency assumes a 100%
inhalation absorption rate (Lacayo, 1984).

-------
                            11-94

     3)  Calculate the Lifetime Average Daily Dose (LADD)
using the formula

                LADD = (Dose acquired in 1 working day in
                       mg/kg/day)

                     x (No. of days exposed per year/365)

                     x (35 years of working)/(70 years
                       lifetime).

     4)  Calculate the LADD risk using the formula

     LADD Risk = LADD x Q±* j where Q±* = 2.3 x 10~3 (mg/kg/day)"1

     In calculating exposure, it is assumed that farm workers
may work from a low of 1 hour to a high of 12 hours per day.
They may wash up immediately after spraying, or not until the
end of the work day.  Steps 1 thru 4 assume an 8-hour work
day (with the exception of Almonds and Home Gardens) and a
steady accumulation of the chemical on the skin throughout
the day.  It is also assumed that workers wash immediately
at the end of the 8-hour work day-

     The mixer/loader and applicator risks for crops are
given in Tables 20 and 21.  Risks for workers with protective
clothing can be obtained from these tables by multiplying
them by 0.2.  It can be seen from these tables that potential
oncogenic risk to applicators from dermal and inhalation
exposure to captan ranges from a maximum of 10~^ (B2) (e.g.,
apples, pre-harvest) to 10~7 (B2) (home gardens and pilots for
almond applications).  The oncogenic risk to mixer/loaders
ranges from 10~5 (B2) to 10~7 (B2).  As can be seen in Tables
10 and 11 in Section II.C.3.a.l. of this document, dermal
exposure far exceeds respiratory exposure for applicators and
for mixer/loaders; the estimates, therefore, in Tables 20 and
21 represent potential risk largely due to dermal exposure.
However, in some cases, as in cranberries, the inhalation
exposure is not insignificant and does add appreciably to
total risk.

     These estimates reflect the upper limit of excess cancer
risk which is not likely to be exceeded.

-------
                         11-95
         Table 20 - Mixer/Loader Risk Estimates
(No Protective Clothing)
Maximum Number of Days Maximum Lifetime
Fruit Crops of Exposure per Year Average Daily Dose Risk1/
Almonds
Apples (preharvest)
Apples (postharvest)
Apricots
Avocado
Blackberry
Blueberry
Cherries
Citrus
Cranberry
Grapes
Mangos
Nectarine
Peaches
Pears
Plum
Pineapple
Vegetable Crop
Beans
Beets
Carrots
Celery
Cucurbits
Eggplant
Lettuce
Peppers
Potatoes (foliar)
Potatoes (seed treat.)
Rhubarb
Soybeans (seed treat.)
Spinach
Sweetcorn
Tomatoes
Ornamentals
Azaleas
Begonias
Carnations
Mums
Diconda (CA)
Turf
Roses
Flowers
2
10
30
4
4
5
10
10
2
3
6
12
5
5
4
7
8

8
7
8
13
13
14
8
20
17
5
10
2
4
10
13

4
12
20
20
3
20
20
15
10-s to 10-0
10-6
10-6
10-6
10-6
10-6
10-5 to 10-6
10-5 to 10-6
10-6 to 10-7
10-6
10-6
10-5 to 10-6
10-6
10-6
10-6
10-6
10-6

10-6
10-6
10-6
10-5 to ID'6
10-5 to 10-6
ID"5 to 10-6
10-6
10-5 to 10-6
10-5 to 10-6
10-6 to 10-7
10-5 to 10-6
10-6 to 10-7
r
ID'6
10-5 to 10-6
10-5 to 10-6
_ _ /-
10~6
10-5 to 10-6
10-5 to 10-6
10-5 to 10-6
10-6
10-5 to 10-6
10-5 to 10-6
10-5 to 10-6
Captan is classified as a Probable Human Carcinogen
(Group B2) in accordance with the Agency's Proposed
Guidelines (U.S. EPA, 1984, 49 FR 46294).

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                      11-96
Table 21 - Applicator Exposure and Risk Estimates
(No Protective Clothing)
Arrival
Rate r
Fruit Crops (mg/hr)
Almonds (pilot)
Apples
(pre-harvest )
Apricots
Avocado
Blackberry
Blueberry
Cherries
Citrus
Cranberry
Grapes
Mangos
Nectarine
Peaches
Pears
Plum
Pineapple
Vegetable Crop
Beans
Beets
Carrots
Celery
Cucurbits
Eggplant
lettuce
Peppers
Potatoes —
(foliar)
Potatoes —
(seed treatment)
Rhubarb
Spinach
Strawberries
Sweetcorn
Tomatoes
Borne and Garden
Ornamentals
Azaleas
Begonias
Carnations
Mums
2.27

30.0
35.0
35.0
24.0
24.0
35.0
35.0
24.0
24.0
40.0
40.0
40.0
28.0
30.0
24.0

24.0
24.0
24.0
24.0
24.0
24.0
24.0
24.0

24.0

0.35
1.7
24.0
24.0
24.0
24.0
1.7

24.0
24.0
24.0
24.0
Dermal V
(rag/day)
0.4

8.014
9.35
9.35
6.4
6.4
9.35
9.35
6.4
6.4
18.2
10.7
10.7
7.5
8.0
6.4

6.4
6.4
6.4
6.4
6.4
6.4
6.4
6.4

6.4

0.09
0.77
6.4
6.4
6.4
6.4
0.45

6.4
6.4
6.4
6.4
Inn
(rag/day)
neg.

0.06
0.06
0.06
0.06
0.06
0.06
0.06
0.06
0.06
0.06
0.06
0.06
0.06
0.06
0.06

0.06
0.06
0.06
0.06
0.06
0.06
0.06
0.06

0.06

0.20
0.0017
0.06
0.06
0.06
0.06
0.0017

0.06
0.06
0.06
0.06
Maximum3/4/5/
Lifetime
Dose2/ Maximum Average Daily
(mg/kg/day) Days Dose Risk
.006

.115
.134
.134
.092
.092
.134
.134
.092
.092
.154
.154
.154
.108
.115
.092

.092
.092
.092
.092
.092
.092
.092
.092

.092

.004
.035
.092
.092
.092
.092
.067

.092
.092
.092
.092
2

10
4
4
5
10
10
2
3
6
12
5
5
4
7
8

8
7
8
13
13
14
8
20

17

5
10
4
10
10
13
4

4
12
20
20
10-7

10-5 to 10~6
10-6
ID"6
10-6
ID"6
10~5 to 10"6
ID"6 to 10~7
ID"6
ID'6
ID"5 to ID'6
10-6
10~6
10-6 to ID"7
ID"6
10"5 to 10"6

10~6
10-6
10~6
10-5 to 10-6
10-5 to 10-6
10-5 to 10~6
ID'6
10-5 to 10-6

10-5 to 10-6

10-7
10-6 to 10-7
10-6
10"6
ID"5 to 10-6
10-5 to 10-6
10-7

10~6
10-5 to 10-6
10"5 to lO"6
10-5 to 10-6

-------
Table 21 - (continued)
                                      11-97

Fruit Crops
Diconda (CA)
Turf
Roses
Flowers

Arrival
Rate r
(mg/hr)
24.0
24.0
24.0
24.0

Dermal V
(mg/day)
6.4
6.4
6.4
6.4

Inn
(mg/day)
0.06
0.06
0.06
0.06

DoseV
(mg/kg/day)
.092
.092
.092
.092

Maximum
Days
3
20
20
15
Maximum3/4/5/
Lifetime
Average Daily
Dose Risk
10~6
10-5 to 10-6
10~5 to 10~6
10~5 to 10-6
I/ Based on A(h,a,r) = r[(h+l)-(l/a)(l-(l-a)h+l)] with h = 6 hours,r = arrival rate,
   a = 1.3% dermal absroption rate,  and a 100% inhalation absorption rate.

2/ Dose =  (Dermal + Inh)/70  (mgAg/day)

3/ Maximum LADD Risk = Qj* Dose x  (# exposed day/365) x (35/70)

4/ Captan  is classified as a Probable Human Carcinogen (Group B2) in accordance
   the Agency's proposed guidelines  (U.S. EPA, 1984, 49 FR 46294).

5/ Lacayo, 1985.  Risks for  workers  with protective clothing can be obtained by
   multiplying the risks by  0.2.

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                            11-98

        c.  Risk to Fieldworkers

     The risk estimates for fieldworkers were calculated
using exposure data on strawberries (Adams, 1984) described
previously in this position documented in Section Il.C.l.b.
The following formulas were used (Lacayo, 1984):

            1)  Estimate of Daily Dermal Exposure

                 Total Agent Absorbed = A (h,a,r)

                 = r [(h + 1) - (I/a) (l-(l-a)h + 1)]

                 where r = arrival rate of agent in grams per
                           hour.

                       h = total number of hours exposed.

                       a = absorption rate per hour of the
                           amount of agent present (1.3%
                           per hour based on Zendzian, 1982
                           and Lacayo, 1984).

                 The worker dose in mg/kg/day is A(h,a,r)/70.

            2)  Estimate of Life Time Average Daily Dose (LADD)

                LADD = (Dose acquired in 1 working day in
                       mg/kg/day)

                     x (No. of days exposed per year/365)

                     x (35 years of working)/(70 years
                       lifetime).

            3)  Estimate of LADD Risk

            LADD Risk = LADD x Q-,^* = LADD x (2.3 x 10~3) (mg/kg/day )-1

     Table 22 presents the exposure and LADD (Lifetime Average
Daily Dose) for the seven field exposure studies using residues
after application of captan on strawberries.  The risk
estimates presented reflect the upper limit of excess  cancer
risk which is not likely to be exceeded (Lacayo, 1984b).

     The order of magnitude of risk is unchanged by:

     1.   Adding the worker dietary risk to the harvest-
ing exposure risk.

     2.   Having workers both pick and weed strawberries, as
in study #3.

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                                 11-99
       Table 22 - Fieldworker Exposure and Risk  Estimates for Seven
       Strawberry Exposure Studies (Adamsf  1984  and Lacayo, 1984b)
Study #
1
2
3 Picking
Vfeeding
4
5
6
7
Arrival
Rate
(mg/hr)
6.5
4.7
17.41
94.13
16.37
5.88
39.01
7.15
Expc
hrs/day
8
8
8
8
8
8
8
8
jsure
day/yr
80
30
80
10
80
80
80
80
Absorp.
per day
mg/kg/day
.04276
.030488
.1129
.61060
.106189
.038142
.25305
.04638
Lifetime
Average
Daily Dose
.00528
.00143
.01414
.009559
.01329
.004779
.031693
.0058
> Risk1/
10-5
10-6
10-5
10-5
10-5
10-5
10-5 to 10~4
10-5
Captan is classified as a Probable Human Carcinogen (Group B2) in
accordance with the Agency's Proposed Guidelines (U.S. EPA, 1984,
49 FR 46294).

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                            11-100

        d.  Risk to Workers in Cut Flower Production

     The risk estimates to workers mixing, loading and spraying
formulations containing captan to flowers and to workers
cutting and packaging the flowers were calculated using the
exposure data described previously in this document in Section
II.C.4.d.  The Agency assumes that workers will be exposed
over a working lifetime of 35 years.   The exposure and risk
estimates using Q^* = 2.3 x 10~3 (mg/kg/day)~1 (Saito, 1985)
are presented in Table 23.

            Table 23 - Exposure and Risk Estimates
             for Workers in Cut Flower Production

                      Exposure (mg/kg/day)         Risk
Operation	Dermal   Inhalation   Dermal	Inhalation

Mix/load/spray         0.19      0.002      10~7(B2)      10~7(B2)

Cutting/packaging      0.09      neg.    10~6 to 10~7(B2)    neg.


        e.  Non-Agricultural Uses

     Captan is used in plastics, adhesives, paints, cosmetics,
and shampoos as an antifungal agent.   The potential oncogenic
risks associated with these exposures have been calculated by
the Agency to range from negligible (e.g., plastics) to
10~5(B2)  (e.g., oil-based paints and animal shampoos (Lacayo,
1985).

     Regarding cosmetics and shampoos for humans, EPA will
transmit all toxicity information to FDA for evaluation and
risk assessment purposes, since FDA regulates these products.
Because dog and cat shampoos are regulated by EPA, a risk
assessment has been calculated for humans who wash their dogs
and cats.

     As can be seen from Table 24,  the potential oncogenic
risk to applicators for plastics, paints, and cosmetics is
negligible; the risk associated with application of captan to
adhesives is 10~5 (B2).  Table 25 shows that potential oncogenic
risks to users of end products containing captan range from 10~4
(B2) (animal shampoos) to 10~9 (B2) (aerosol sprays).  For
dog or cat shampoos, the risk to humans is 10~4 to 10~5 (B2)
assuming lOg on the skin at a 0.25% concentration (25mg/day),
a person shampooing a dog 4 times a year for 60 years out  of
a 70 year lifetime, at 100% absorption.  The estimated risks
reflect the upper limit of excess cancer risk which is not
likely to be exceeded.

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                              11-101

  Table 24 - Risks during Application for Non-Agricultural Uses

Use
Exposure
(mg
/kg/day)
On* - 2.
Risk
3xlO"3
(mg/kg/day)
 Plastics [1]
 Adhesives [2]
 Paints  [1]
 Cosmetics [1]
 negligible
 0.162 (i+d)
 negligible
j negligible
|negligible
JIG"5 (B2)
j negligible
|negligible
 [1]   The Mitre Report (1981) states that gloves, respirator (dust
 »     masks for cosmetics incorporation) and protective clothing
      are normally worn during application/ mixing; thus the
      exposure and risks are negligible.

 [2]   Assumes 70 kg person, 2.5 minutes application/hour, 72 days/
      year for 40 years of a 70 year lifetime.
      For inhalation  (i) exposure estimate, assume 100% absorption,
      10 mg/day.
      For dermal (d) exposure estimate, assume 1.3% absorption of
      amount present per hour and 200 mg/day exposure.

      Table 25 - Risk from Product Use  (Non-Agricultural)V
Use
Plastics
Adhesives
Home Use2/
Professional-^/
Paints
Oil-based4/
Water-based^/
Shampoos
for animals6/
Mattresses^/
Aerosol sprays^/
Pet powders 9/
Powdered hand
soaplO/
Exposure (mg/kg/day )
negligible
0.0624
0.0624
0.857
0.089
0.416
0.013 (dermal)
0.00036
0.014
0.016
Risk
Q-L* =2.3xlO-3 (mg/kg/day p1
negligible
ID"6 to 10~7
10-5
10-5
10-6
10-4 to 10-5
lO"5 to 10"6
10-9
10-8
10-5 to 10-6
V  Captan is classified as a Probable Human Carcinogen (Group B2)
    in accordance with the Agency's Proposed Guidelines (U.S. EPA, 1984,
    49 FR 46294).

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                              11-102

(Footnotes to Table 25 continued)

2/  For home use of adhesives,  assume a 60 kg person,  36 mg/day
    dermal exposure, 8 hours/day,  2 days/year for 40 years of a 70
    year lifetime, 1.3% dermal  absorption per hour.

3/  For professional use of adhesives, assume a 60 kg person, 36
    mg/day dermal exposure, 8 hours/day,  100 days/year for 40 years
    of a 70 year lifetime 1.3%  dermal absorption/hour.

4/  For oil-based paints, assume a 60 kg  person,  60 mg/day dermal
    exposure, 8 hours/day, 10 days/year for 40 years of a 70 year
    lifetime and 100% dermal absorption due to oil base or
    varnish as a vehicle containing the captan.

5/  For water-based paints, assume a 60 kg person, 60 mg/day
    dermal exposure, 8 hours/day,  10 days/year for 40 years of
    a 70 year lifetime and 1.3% dermal absorption per hour.

*>/  For shampoos (dog or cat being washed by a person) assume a
    60 kg person, 50 mg dermal  exposure per day (10 g  shampoo x
    0.5% W/W = 50 mg), 4 times  a year for 60 years of  a 70 year
    lifetime and 100% dermal absorption due to the presence of
    oil/water emulsion, glycerine, or triethanolamine  stearic
    acid soap.

"V  For mattresses in nursing homes, assume a 60  kg person, 6.0
    mg/day dermal exposure at 1.3% dermal absorption per hour, 10
    years in a nursing home over a 70 year lifetime.  The Agency
    assumes that coverings will reduce the exposure at least by
    an order of magnitude.

8/  For aerosol sprays, assume  negligible inhalation exposure,
    0.3 mg/hr (mean dermal exposure at 100% dermal absorption)
    for 5 minutes once a weffk throughout  the year for  35 years
    of a 70 year lifetime.

9/  For human exposure to pet powders, assume negligible inhalation
    exposure, 200 mg dermal exposure (at  100% dermal absorption)
    per use once a week throughout the year for 35 years of a
    person's 70 year lifetime.

10/ For a sanitizing powdered hand soap,  assume a 60 kg person,
    87 mg/day exposure at 1.3%  dermal absorption, twice a week
    for 35 years out of a person's 70 year lifetime.

            f.  Uncertainties in the Risk Assessment

       The risk assessment approach contains a number of uncertain-
  ties.

       The quantitative risk estimates contain a  great deal of
  uncertainty because they must necessarily extrapolate from
  laboratory animals to humans  and from the very  high exposures

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                             11-103

used in the laboratory studies to the generally much lower and
less well characterized human exposures.  The Agency's approach
has been to present plausible upper bounds to the risk as a
rough indication of what the potential risks might be.

     Dietary exposure estimates are a source of uncertainties,
some of which have been discussed in section II.C.4.a.(4 and 5.)
Tolerance levels were used to calculate a worst-case risk
estimate.  Insufficient data are available on residues likely
to be present on food as consumed.  In order to avoid suspension
under FIFRA 3(c)(2)(B) data call-in provisions, the registrant
must submit such data in the near future.

     Variation  in individual food intake patterns is another
source of uncertainty in estimating health risks from dietary
exposure to captan.  The dietary burdens in the dietary exposure
tables (Tables  14 and 15) were based upon standard food factors
used by the Agency for many years to represent typical diets.
Although these  standard food factors are appropriate for
estimating average population risk, some individuals and
subgroups within the population will be at greater (or lesser)
risk because their diets contain more (or less) of the food
with captan residues.

     Similarly, there are variations in the amount of food
consumed as a "single serving".  The Agency calculated the
"single serving" from information available in the USDA report,
"Family Food Buying (USDA, 1977).

     Uncertainties also exist in the area of applicator exposure
and risk, and the primary uncertainty in this area relates to
time spent in applying captan, the number of applications made
per year, the duration of each application, and the number of
years a person  would be applying captan are all highly variable.

D.  TERATOGENIC RISK ASSESSMENT

     The "single serving" dietary exposure assessment, as
described in Section Il.C.S.a., makes it possible to calculate
teratology margin of safety (MOS) for captan dietary exposure
(Schneider, 1982).

     The results of a study using Syrian Golden Hamsters (Robens,
1970) were suggestive for teratogenic effects with a no-observed-
effect-level (NOEL) of 200 mg/kg/day.  The allowable daily
intake for a 60 kg woman would be 12,000 mg/day (200 mg/kg/day x
60 kg).  The lowest MOS is 828 for cherries (Table 26).  However,
because there were omissions and/or inconsistencies in the
tabular data and because statistical analyses were not performed
in this study,  the Agency will require an additional teratology
study in hamsters to better evaluate these effects.

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                          11-104
Table 26 - Teratogenic Margins of Safety for Various Crops
             From Dietary Exposure to Captan
Food Commodity
or Grouping
Almonds
Apples
Apricots
Avocados
Beans, Lima (Fresh)
Bean, Snap (Fresh)
Beet Greens
Beets
Blackberries
Blueberries
Broccoli
Brussels sprouts
Cabbage, Sauerkraut
Cantalopes
Carrots
Cauliflower
Celery
Cherries
Collards
Corn, Sweet
Cottonseed
Crabapples
Cranberries
Cucumbers, Pickles
Dewberries
Eggplant
Garlic
Grapefruit
Grapes
Raisins
Honeydew melons
Kale
Leeks
Lemons
Lettuce
Limes
Mangoes
Muskmelons
Mustard greens
Nectarines
Onions, dry bulbs
Onions, green
Oranges, juice
Peaches
Pears
Single Serving!/
(kg)
Unknown
0.212
0.114
0.150
0.072
0.055
0.076
0.080
0.072
0.072
0.092
0.078
0.090
0.160
0.110
0.115
0.120
0.145
0.095
0.080
Unknown
Unknown
0.070
0.144
0.072
0.100
0.003
0.101
0.080
0.145
0.170
0.055
Unknown
0.016
0.057
0.016
0.082
0.160
0.070
0.150
0.171
0.025
0.245
0.152
0.180
Tolerance
(ppm)
2.00
25.00
50.00
25.00
25.00
25.00
100.00
2.00
25.00
25.00
25.00
2.00
2.00
25.00
2.00
2.00
50.00
100.00
2.00
2.00
2.00
25.00
25.00
25.00
25.00
25.00
25.00
25.00
50.00
50.00
25.00
2.00
50.00
25.00
100.00
25.00
50.00
25.00
2.00
50.00
25.00
50.00
25.00
50.00
25.00
Daily Intake
(mg/dayX
_
5.30
5.70
3.75
1.80
1.38
7.60
0.16
1.80
1.80
0.18
0.16
0.18
4.00
0.22
0.23
3.00
14.50
0.19
0.16
-
-
1.75
3.60
1.80
2.50
0.08
2.50
4.00
7.25
4.25
0.11
-
0.40
5.70
0.40
4.10
4.00
0.14
7.50
4.28
1.25
6.12
7.60
4.50
(MOS)2/
_
2264
2105
3200
6667
8696
1570
75000
6667
6667
66667
75000
66667
3000
54546
52174
4000
828
63158
75000
-
-
6857
3333
6667
4800
15000
4800
3000
1655
2824
109091
-
30000
2105
30000
2927
3000
85714
1600
2804
9600
1961
1579
2667
Peas, dried 0.200 2.00 0.40 | 30000

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                                    11-105
Table 26 (continued)
Food Commodity
or Grouping
Peppers
Pimentos
Pineapple
Plums, prunes
Potatoes
Pumpkin
Quinces
Raspberries
Rhubarb
Rutabagas
Shallots
Soybeans (Curd)
Spinach
Winter Squash
Strawberries
Summer Squash
Tangerines
Taro
Tomatoes
Turnips
Turnip Greens
Watermelon
Single Serving!/
(kg)
0.100
0.018
0.084
0.070
0.169
0.245
Unknown
0.072
0.122
0.120
0.010
0.120
0.055
0.222
0.075
0.120
0.100
Unknown
0.181
0.130
0.072
0.160
Tolerance
(ppm)
25.00
25.00
25.00
50.00
25.00
25.00
25.00
25.00
25.00
2.00
50.00
2.00
100.00
25.00
25.00
25.00
25.00
0.250
25.00
2.00
2.00
25.00
Daily Intake
(mg/day)
2.50
0.45
2.10
3.50
4.22
6.12
—
1.80
3.05
0.24
0.50
0.24
5.50
5.55
1.88
3.00
2.50
-
4.52
0.26
0.14
4.00
(MOS)2/
4800
26667
5714
3428
2844
1961
_
6667
3934
50000
24000
50000
2182
2162
6383
4000
4800
-
2655
46154
85714
3000
  I/  Source: USDA, 1977
      Margin of Safety

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                             11-106

E.  REPRODUCTIVE RISK ASSESSMENT

     Section II.B.2. presented laboratory animal studies which
showed that captan caused impaired growth of offspring.  The
NOEL for toxic effects seen in the reproduction studies is 12.5
ing/kg/day and the lowest-effect-level (LEL) is 25 mg/kg/day.
To determine whether there is an adequate margin of safety
(MOS) between the NOEL for toxic effects and dietary residue
levels to which humans might be exposed, the Agency made the
following calculations:

  - The allowable daily intake (ADI) based on the NOEL of
12.5 mg/kg/day and a safety factor of 100 would be 0.125
mg/kg/day.

  - For a 60 kg person, the ADI translates into a maximum
permissable intake (MPI) of 7.5 mg/day.

  - The theoretical maximum residue contribution (TMRC) assumes
that an average person consumes an average (1.5 kg) daily diet
with the crops containing tolerance levels of the captan residues,
The TMRC is 12.2 mg/day.

  - The TMRC exceeds the ADI by 63%.  The Agency recognizes
that dietary residues may not occur at tolerance levels, no
data are available to allow better estimation of the actual
dietary residues.  When such data are submitted, the Agency
will reassess the established tolerances.

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                    III.  BENEFITS SUMMARY

A. INTRODUCTION

     Captan is a fungicide produced domestically and is also
imported from Israel and Taiwan.  Total usage of captan in
the United States is estimated at 9 to 10 million pounds
active ingredient per year.  Treatment sites include apples,
peaches, almonds, soybean seeds, strawberries, corn, potato
seed pieces, cotton, sorghum, peanuts, and numerous other
crops (Table 1).

     The information used to estimate the benefits of captan
was derived from several sources -  the U.S. Department of
Agriculture, States, and EPA assessment report (Jacobsen, 1982;
team leader), the Chevron and Stauffer Chemical Companies
(Chevron, 1980, Stauffer, 1980), and analyses produced under
cooperative agreements between the EPA and various State
Universities (Anderson and Allison, 1983; Drake et al. 1981;
Gait et al. 1983; Grube, 1983; Norton et al. 1982; Ofiara et
al. 1983; and Wichelns et al. 1982).  The general approach
of this analysis was to evaluate the economic impacts of a
captan cancellation causing users to shift to alternative
disease control programs.  The alternatives to captan were
chosen on the bases of cost, efficacy, and market availability.

     Economic impacts on society, as well as for users and
consumers, were based on changes in production costs, crop
yield reductions, and possible grower shifts to other enterprises.
Impacts on users were considered on a per-unit and per-establishment
basis as well as at the state, regional, and national levels.
Grower level impacts were then utilized for projections at the
commodity market levels.  The commodity market impacts were then
used for estimating the distribution of impacts among consumers,
users, and non-users.  The sensitivity of these estimates to
changes in disease control data and production losses have
been examined and indicate these estimates are most representative
of the expected impacts.

     Cancellation of all current uses of captan are expected
to result in first year lost benefits of $20 to $44 million
at the farm level, which represents both increased costs of
disease control and decreased value of production.  In calculating
these impacts, it was assumed that only currently registered
pest control methods would be available at the time of a
captan cancellation.  It is expected that for fruits and
vegetables the burden would be largely borne by the consumer
since large portions of the crops are treated, and market
conditions are such that the economic impacts could be transmitted
through the marketing system to the retail level.  For seed
treatment it is expected the burden would be borne by the
farmer or seed conditioner since marketing conditions are
indicative of excessive supply for produced commodities.

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                                   III-2
            Table 1.  Estimated Captan Usage and Benefits of Use
Site
Captan use ~ Acres
(pounds a.i.) planted
(1,000) (1,000)
Acres
treated
(1,000)
Annual impact
Total
($1,000)
Per Acre
($)
Fruits and Vegetables
Apples
Almonds
Bushbe tries
Apricots
Nectarines
Peaches
Pineapples
Strawberries
Others
2,934
897
109-148
128-160
108-135
1,092
11
669-870
338-565
500
317
71
25
16
188
44
36
NA
169-172
188
19-23
17
11.6
121
9
30
120
900 to 3,300
1,405
3,500 to 4,000
-434 to 700
-1 to 654
2,300 to 5,000
0 to 3,775
5,950
1,200 to 3,000
5.30 to 19.60
7.47
174.00 to 184.00
-25.53 to 41.18
-0.09 to 56.38
19.00 to 41.32
0.00 to 413.92
198.73
10.00 to 26.67
Seed Treatments a/
Corn
Cotton
Sorghum
Soybeans
Peanuts
Rice
Small Grains
Potatoes
Vegetables
Other Sites
Home Gardens
676
275
100
880
76
22
97
565
235

100
Forest Nurseries 6
Turf
Ornamentals
24 14
45-50
81,000
14,000
14,500
73,620
1,350
3,000
96,777
1,300
NA

NA
17
,000-54,000
NA
Total 9,387-9,918



81,000
11,500
10,400
1,400
0
1,900
14,300 -6,200 to 3,400
770
309
2,800
377
NA

NA
1
5
NA
146
35
391
-192 to 532
up to 1,500

NA
-155 to 1,557
28
6,000 to 12,600
0.02
0
0.10
-0.43 to 0.24
0.19
0.17
0.14
-0.51 to 1.41
NA

NA
NA
5.60
NA
20,000 to 44,000
a/ The ranges  for  the grains in this section are somewhat misleading
Ąince captan is applied largely by seed suppliers who use captan for a
number of different types of seed rather than contend with varying use
practices for  several types of fungicides.

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                            III-3

Impacts on ornamental growers would be borne by the grower
since they are already facing substantial foreign competition.
Data were not available to estimate whether the burden for
forest nurseries and turf would be borne by the user or others.

B. FRUITS AND VEGETABLES

     1.  Apples

     The largest use of captan is for apples, which represents
about 30 percent of the total annual usage.  Captan is used
for control of disease causing fungi on about 170,000 acres
of apples or about 34 percent of U.S. commercial apple production

     The loss of captan could result in annual losses of $900,000
to $3,300,000 from the decreased control costs ($600,000 to
$900,000) due to lower cost of alternative fungicides and the
decreased value of about 40 million pounds of fruit ($1.5 to
$4.2 million) annually being diverted from the fresh to the
processed market because of increased disease damage with use
of alternatives.  The following fungicides, within given
limitations, are considered to be viable alternatives: metiram,
maneb, mancozeb, zineb, thiram, folpet, captafol, dichlone,
triforine, and fenarimol.  None of the captan alternatives
are registered for control of all the apple diseases controlled
by captan and some are registered for control of only a few
of the diseases for which captan is registered.

     A product mixture, Dikar®, containing mancozeb and dinocap
is one of the most effective alternatives to captan for use on
apples.  This mixture is effective against most of the major
apple diseases controlled by captan and also controls powdery
mildew and rust disease for which captan does not provide
adequate control.  In Eastern apple production areas where
there is a high incidence of heavy apple scab disease, captafol
and dichlone are applied in early season application and
Dikar® is applied for the remainder of the season.

     The primary alternative fungicides expected to be employed
are metiram and mancozeb.  Use of these alternatives could
cause farm level prices to rise by $0.084 per bushel for
fresh fruit due to decreased quantities of apples in the
fresh market and an ensuing decline of $0.042 per bushel for
processing apples due to increased quantities of apples
diverted to this market.  The new farm level prices could
result in increased revenues for growers not using captan.
Those growers using captan could suffer losses due to reduced
fruit quality associated with Dikar® use.  In the aggregate,
average changes in producer net revenues per acre would range
from a decline of $2.80 to an increase of $2.10.  Based on
average size apple orchards, on a per farm basis, farmers are

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                            III-4

expected to lose on average approximately $530 in net revenues
in the Northeast, and $150 in net revenues in the Southeast,
but gain $280 in the Central region, and $233 in the West.
While these impacts are significant, the farmers facing
losses would typically be able to absorb these impacts without
major effects on the longer term financial viability of the
farms since this represents about a one percent reduction in
gross revenues.

     Retail prices could increase by $0.172 per bushel for
fresh apples due to decreased quantities of apples in fresh
markets and decline by $0.172 per bushel for processing due
to the increased quantities of apples in this market.  Consumer
fresh apple expenditures could decline because of the greater
influence of the reduction in quantity consumed relative to
the expected increase in the retail price.  Consumption of
processed apples would be expected to increase with the
decrease in prices for processed apples.  The decrease in
consumer expenditures for fresh apples is expected to more
than offset the increase in expenditures for processed apples.

     2.  Almonds

     Captan is used on about 188,000 acres of almonds, which
represents about 59 percent of U.S. almond acres.  The loss
of captan use on almonds would result in increased disease
control costs of about $1.4 million annually which would be a
relatively minor impact on the impacted growers since this
represents about one percent of gross income to those
currently using captan.  Data were not available to estimate
the extent these impacts could be shifted to the consumer.

     Captan and thiophanate methyl are viable alternative
controls for brown rot disease while captan and ziram are the
alternative controls for the shothole disease.  Therefore,
the loss of captan would .require use of both materials for
control of the diseases currently controlled by captan.

     3.  Bushberries

     Captan is used for disease control on 26 to 32 percent of
bushberries (blackberries, boysenberries, blueberries, cranberries,
loganberries, and raspberries) acreage.  The loss of captan
would result in annual losses of $3.5 to $4.0 million (increased
disease control costs of $200,000 to $300,000 and production
losses of $3.3 to $3.7 million) to those producers using
captan.  This represents decreased net returns of $174 to
$184 per acre which would represent major losses to the
impacted growers.  These losses represent about 10 percent
of gross revenues for those acres treated with captan and
although net revenue data were not available, data for
other crops indicates this probably would exceed net returns.
Data were not available to estimate consumer impacts.

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                            III-5

     Fruit, leaf and shoot diseases are major problems on
bushberries in many of the growing areas.  Near harvest time
wet weather is particularly conducive to the development of
outbreaks of fruit rots which are likely to cause yield
losses.

     Several fungicides are available which could be used as
alternatives to captan.  These alternatives include difolatan,
2,6-dichloro-4-nitroaniline (DCNA), and triforine.  However,
DCNA is the only potential alternative fungicide which can be
applied near harvest time.

     4.  Pineapples

     Captan is used as a preplant dip treatment for pineapple
rootstock planted on about 20 percent of the 43,000 acres of
pineapples grown in Hawaii.  It is used to prevent diseases
caused by soil borne pathogens.

     Alternatives to captan are Aliette®, fenaminosulf,
mancozeb, and captafol.  Captafol provides equal or superior
protection compared to captan, but is not used as a preplant
dip because planter exposure results in dermatitis.  However,
captafol is widely used as a post-plant spray.

     Without or with only limited use of captafol, the annual
losses associated with a captan cancellation could range up
to $3.8 million due to yield losses.  If captafol were used
as the alternative pineapple production would be maintained
at current levels with essentially no change in production costs
This represents a range in losses of from essentially no
impact to $400 per acre. If losses of $400 per acre resulted,
this could result in some producers shifting out of pineapple
production on the affected acres since it is likely that the
loss would exceed net returns since this loss is about 20
percent of gross returns.  Consumer impacts are not expected
since a large portion of the pineapple consumed is already
imported and domestic producers have to compete with foreign
production.

     5.  Strawberries

     Captan is used on 30,000 acres (about 82 percent of U.S.
strawberry acreage) for control of certain fruit and leaf
diseases.  Alternatives to captan include thiram, benomyl,
vinclozolin, and thiophanate methyl.  Without captan growers
would use some combination of thiram and vinclozolin with an
increase in annual disease control costs of about $5.9 million.
This represents increased costs of almost $200 per acre which
would represent major losses to impacted producers, but may
be passed on to the consumer and would only represent a very
small change in typical household fresh fruit expenditures.

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                            III-6

     6.  Apricots, Nectarines, and Peaches

     Captan is used to control several leaf and fruit
diseases on about 61 percent of the bearing acres of apricots,
nectarines, and peaches grown commercially in the U.S.
Thiophanate methyl, triforine, maneb, benomyl, glyodin, and
sulfur are the alternatives most likely to be used to replace
captan.

     The loss of captan for disease control in apricots would
result in an annual economic impact ranging from a decrease
in control costs of $434,000 to an increase of $700,000
depending on the alternatives selected, number of applications
and application rate.  It is unlikely that widespread decreased
disease control costs would result.

     Nectarine producers could have increased annual disease
control costs of up to $650,000 if captan were no longer
available.

     The loss of captan on peaches could result in annual losses
ranging from $2.3 to $5.0 million due to increased disease
control costs and lost peach production.  Peach producers not
requiring the use of captan would experience windfall gains
from the increase in peach prices while producers requiring
the use of captan would have reduced returns.

     It is likely that the apricot and nectarine losses would
be borne by the producers while a portion of the peach loss could
be shifted to the consumers because of increased peach prices.
Although these peach losses could be significant to impacted
producers, it is likely they would be passed on to the consumer
where the expense would be a very small portion of total
household fruit expenditures.  The apricot and nectarine
losses represent between one and two percent of gross returns
and probably are not a threat to the continued viability
of the industries.

     7.  Other Fruits and Vegetables

     Captan is registered for use on a number of other fruit
crops such as cherries, citrus, grapes, papaya, pears, plums,
prunes, taro, as well as several other vegetable crops.  The
cancellation of captan would result in annual losses ranging
from $1.2 to $3.0 million with expected losses approximately
$2.0 million (costs of disease control ranging from a decrease
of about $400,000 to increased disease control costs of about
$1.1 million depending on the alternative fungicide used;
and value of production losses of $1.6 to $1.9 million).
Data were not available to estimate whether any of these
potential losses would be shifted to the consumer.  Although
data were limited for the loss of captan for these uses, it
is unlikely that individual producers or the various industries
would be faced with major losses.

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                            III-7

     Alternatives to captan include: benomyl, thiophenate-methyl,
dodine, dichloran, triforine, and chlorothalonil on cherries;
captafol, chlorothalonil, and coppers on citrus; ferbam,
maneb, mancozeb, dinoseb, sodium arsenite, dichloran, triadimefon,
and fenarimol on grapes; ferbam, sulfur, dichlone, coppers,
triademefon, chlorothalonil, dichloran,  and ziram on plums
and prunes with severe efficacy limitations; coppers on
avocados; maneb, chlorothalonil, dichloran, and coppers on
beans; zineb, ziram, and coppers on beets; captafol, folpet,
chlorothalonil, metalaxyl, dichloran, mancozeb, and maneb on
cucurbits; chlorothalonil, mancozeb, maneb, and zineb on
carrots; analazine, folpet, chlorothalonil, dichloran, mancozeb,
maneb, and zineb on celery; mancozeb, maneb, and zineb on
eggplant and peppers; folpet, maneb, zineb, dichloran, and
vinclozolin and lettuce, captafol, chlorothalonil, metalaxyl,
triphenyltin hydroxide, metiram, mancozeb, and maneb on potatoes;
folpet, dichloran, captafol, mancozeb, maneb, and zineb on
onions; captafol, metiram, chlorothalonil, folpet, maneb,
mancozeb, metalaxyl, and zineb on tomatoes; chlorothalonil,
maneb, and zineb on spinach; and dichloran on greenhouse
rubarb.

C.  SEED TREATMENTS

     Captan is used as a seed treatment for a variety of crops
with the major use being field corn where nearly all of the
planted seed is treated with captan.  Major portions of the
peanut, sorghum, and soybean seed, and seed piece potatoes
are also treated with captan.  Other seeds treated include
barley, oats, rice, rye, and various vegetables.  Estimated
losses would be less than 50 cents per acre for all producers
except sorghum producers where losses could be about $1.00
per acre.  These losses represent minor impacts to the
farmers using captan treated seed.  The range of estimated
losses are somewhat misleading since captan is applied largely
by seed suppliers who use captan for different types of seed
rather than contending with varying use practices for several
types of fungicides. This practice achieves cost savings for
the seed suppliers since shifting from one fungicide to
another in the treatment boxes would involve the costs of
down time and cleaning treatment boxes which would be considerable
to the seed treatment industry as a whole.  Estimating the
economic value of this convenience was beyond the scope of
this analysis.

     1.  Corn

     An estimated 676,000 pounds of captan are used annually
to treat virtually all of the field corn and 75 percent of
the sweet corn seed planted in the U.S.  Thiram is the altern-
ative currently registered which is most likely to be used if
captan use were cancelled since it was the seed treatment of
choice prior to the availability of captan.  Even though

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                            III-8

thiram has been implicated in human dermatitis problems,
available information indicates it still would be the preferred
alternative.

     Thiram could be used to replace captan with an annual
increased treatment cost of about $1.4 million or about $0.02
per acre planted.  Virtually all of the seed is treated by
the seed suppliers and the increased cost would be either
borne by the seed suppliers or corn producers.

     2.  Cotton

     Captan is currently used to treat about 80 percent of the
seed planted on approximately 14 million acres of U.S. cotton.
In addition, a relatively minor quantity of captan is applied
to the soil as a supplementary treatment when cool wet conditions
are present at planting.  Captan is usually applied in combin-
ation with another fungicide, such as carboxin, chloroneb, or
fenaminosulf to provide broader spectrum disease control.

     All cottonseed used in the U.S. is treated with fungicides
by seed companies as a measure to reduce the probability of
disease.  With good soil conditions, seed treatment will
provide adequate protection.  However, when the soil is cool
and wet at planting a supplementary soil treatment is necessary
to insure a good stand.  The likely alternatives to captan
are captafol, 2-(Thiocyanomethylthio)benzothiazole (TCMTB),
and thiram.  It is expected that any of these alternatives
would be mixed, as is captan, with other fungicides such as
carboxin, chloroneb, and fenaminosulf.

     Based upon current recommendations of cotton producing state
extension plant pathologists, as well as cost, the likely
alternative if captan use is cancelled is thiram.  Any change
in yield or change in cost associated with this substitution
should be negligible.  PCNB plus 5-Ethoxy-3-trichloromethyl-
1,2,4-thiadiazole (ETCMTD) mixtures are likely to substitute
for captan as a supplementary soil treatment with the cost
approximately equal to captan.

     3.  Sorghum

     Captan is used to treat sorghum seed for planting about 10.4
million acres of sorghum.  This represents about 94 percent of
the U.S. sorghum acres planted.

     Seed treatment with captan controls a wide range of seed
and seedling diseases.  Potential alternatives to captan include
mancozeb, PCNB, TCMTB, and thiram.  Of these fungicides,
thiram is the most likely alternative to be used in place of
captan.

     The annual cost of treatment would increase by about
$51,000 with thiram or about $0.02 per acre.  With the use of

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                             III-9

thiram there would be a 0.1 percent decrease in yield on
those acres currently treated with captan.  This would result
in an annual loss of about $1.9 million with producers bearing
about $1.4 million of the loss and consumers bearing the remaining
$500,000.

     4.  Soybeans

     Captan is used to treat enough soybean seed to plant about
20 percent (about 14.3 million acres) of the U.S. soybean
acreage.  Captan is used as a control for various seed decay
and seedling blight organisms.  Potential alternatives to
captan include maneb, PCNB with ETCMTD, carboxin with thiram,
and thiram.

     It was estimated that the annual costs of seed and seedling
disease control would decrease by $6.2 million or increase by
$3.4 million depending on the combination of alternatives
adopted.  No changes in crop yield or quality are expected.
The per acre impact ranges from an increase in profits of
$0.40 to a decrease of $0.24 which are expected to have negligible
effects on farm management decisions.  In the absence of any
significant increase or geographical shifts in soybean acres,
it is unlikely that any of the expected changes would be shifted
to consumers.

     5.  Peanuts

     Captan is applied to about 56 percent of the U.S. peanut
seed as a control of seed and seedling diseases of peanuts.
Captan is usually combined with other chemicals for application
as a seed protectant.  potential alternatives to captan
include DCNA, captafol, carboxin, and thiram.  At least one
of the alternatives could be used to replace captan without a
reduction in yield.

     It was estimated that a loss of captan would result in
increased costs of production of about $146,000 annually.
Since this amounts to about a $0.19 per acre increase in
disease control costs, it is unlikely that any of the increased
costs would be shifted to consumers.

     6.  Rice

     Captan is used to treat about 37 percent of the rice seed
used in California.  This represents about  309,000 acres of
rice or about 10 percent of the rice acres harvested in the
U.S.  Captan is used as a treatment for various seed and
seedling disease causing organisms.  Potential alternatives
to captan include captafol, carboxin with thiram, cupric
hydroxide, mancozeb, PCNB, TCMTB, and thiram.

     If captan use is cancelled, growers now planting rice
treated with captan would shift to captafol without any yield

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                            111-10

impacts.  Fungicide costs would increase by about $35,000 annually
or about $0.11 per acre.  It is expected that the producer
would absorb these cost increases without any impact on the
consumer.

     7.  Small Grains

     Captan is registered for use on barley, oats, rye and wheat
for the control of a variety of seed and seedling diseases as
well as smut.  It is estimated that about 2.8 million acres
of these small grains are planted annually with captan treated
seed; this represents 2 to 5 percent of the U.S. acreage for
these crops.

     With a loss of captan some combination of carboxin, maneb,
thiram, TCMTB, maneb, hexachlorobenzene, PCNB, and ETCMTD
would be used with annual treatment costs increasing by about
$391,000 with no change in yields.  On an individual crop
basis, per acre cost changes would range from a decrease of
$0.06 for rye to an increase of $0.14 for wheat.  It is expected
that the producers of these crops would absorb the cost changes
with no impacts on the consumer.

     8.  Potatoes

     Captan is registered for use on potato seed pieces to
prevent infection of seed piece and of emerging seedlings.
It is estimated that 377,000 or 27 percent of the commercial
potato acreage is planted with captan treated seed pieces.
Potential alternatives to captan include maneb, thiabendazole,
ferbam, zineb, and metiram.

     Maneb and mancozeb could be used to replace captan with a
decrease in the cost of seed treatment ranging from $192,000
to $532,000 without any yield impacts.  It is expected that
potato producers would absorb these cost changes with no
impact on the consumer.

     9.  Vegetables

     Captan is also used on a variety of vegetable seeds for
control of various disease causing organisms.  The principle
seeds treated are peas and beans.  Alternatives available
include thiram and fenaminosulf, which can be applied without
any yield reductions.

     Since about 72 percent of U.S. acreage of these crops is
planted with captan treated seed, part of the annual $1.5
million potential increase in costs could be passed on to the
consumer but data were not available to estimate the magnitude.
Regardless of the portion of producer impact that is passed
on to the consumer, the impact on the consumer would be
negligible.

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                            III-ll

D.  OTHER SITES

     1.  Home Gardens

     About 100,000 pounds a.i. of captan are used annually by
home gardeners on a variety of sites ranging from ornamentals
to fruits and vegetables.  Registered alternatives include
benomyl, maneb, zineb, lime sulfur, bordeaux mixture, analazine,
chlorothalonil, and folpet.  Data are not available to estimate
the effectiveness of captan in the home garden setting.  However,
data available for the commercial fruit, turf, and vegetable
sections indicate alternatives could be employed with only
relatively minor yield losses.  There was no attempt to
estimate the magnitude of impacts on home gardens since data
were not available for homeowner use sites.

     2.  Forest Nurseries

     Captan is registered for control of damping-off diseases
in forest nurseries.  Potential alternatives to captan include
thiram, dazomet, TCMTB and ETCMTD plus thiophanate methyl.
Available data indicate that alternatives will provide control
of damping-off that is equivalent to captan.  It is estimated
that captan is annually used to treat approximately 1,250
acres, which represents about 8 percent of the U.S. forest
nursery acreage.

     Per acre control costs for alternatives range from a
decrease of $124 per acre with TCMTB to an increase of $1,246
with thiram.  This indicates that a shift to alternative
controls could result in annual impacts ranging from a decrease
in disease control costs of $155,000 to an increase of $1,557,000
depending on the combination of alternatives selected.  Regard-
less of a gain or loss, the expected impact is negligible.

     3.  Turf

     Captan is used on turf for control of several diseases.
It is estimated that about 5,000 acres of turf are treated
with captan on an annual basis.  This represents less than
one percent of the estimated 14 to 54 million acres of turf
in the U.S.  Thiram is the only alternative which provides
control of a comparable range of diseases.  Use of thiram
would result in an annual increase in total disease control
cost of about $28,000 or about $5.60 per acre which would be
a minor impact.

     4.  Ornamentals

     Captan is also used on a wide range of ornamentals for
control of a large number of diseases.  Although captan is
registered for use on many plant/pest sites, in a number of
cases other chemicals are preferred to captan.  The principal
uses of captan are for control of certain diseases in carnations,

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                            111-12

control of corm rot on gladiolus, and control of selected
diseases on field grown roses.

     Current indications are that 45,000 to 50,000 pounds a.i.
of captan are used on ornamentals.  Benomyl and thiophanate
methyl are the likely alternatives to captan on carnations.
Neither of these alternatives can be used alone for an extended
period of time due to development of disease resistance build
up. Therefore, in the absence of additional alternatives it
is expected that the carnation cutting production industry
would be forced out of business as disease resistance increased
to the remaining fungicides.

     Thiabendazole is used extensively to control corm rot on
gladiolus and would provide control equal to captan.

     Benomyl, triforine, chlorothalonil, ferbam, zineb, and
folpet provide alternative control of various rose diseases.
Benomyl, chlorothalonil, and zineb providing equal control.

     It has been estimated that the domestic carnation cutting
producing industry (plants produced for flower growers) would
be unable to continue to compete with imported cuttings if
captan were cancelled.  This would result in a short term
annual loss of about $6,000,000 which would decrease as an
alternative use is found for the resources currently devoted
to carnation cutting production.

     If the domestic carnation cutting production industry
managed to survive the loss of captan, carnation cut flower
growers would experience a 33 percent loss of plantings due
to increased disease pressure.  This could result in increased
replanting costs of about $12.5 million.

     The loss of captan for gladiolus corm treatment would
result in cost of control increases of about $40,000 and on
roses would result in cost of control increases of about
$96,000.

     It appears likely that the carnation cut flower industry
would pass a significant portion of the increased costs to
consumers in the form of short run higher prices.  The minor
production cost impacts on gladiolus and rose producers would
not be expected to cause any consumer impacts.

E.  NON-AGRICULTURAL USES

     As discussed in Section II.C.2, there are several "non-
agricultural" uses of captan as a biocide in plastics,
adhesives, paints, and cosmetics.  The latter is regulated by
the Food and Drug Administration.  Alternatives to captan for
these uses exist and are summarized below (Pelletier, 1985).
Though economic assessments of these uses have not been

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                            111-13

conducted, numerous alternatives are registered for each use;
however, there are no registered alternatives for dog and cat
shampoos.  The only alternative for captan in soaps is 4-chloro-
3,5-xylenol.  Listed below are the registered alternatives
for captan for use in oil-based paints, plastics, and wallpaper
flour adhesives.

(3il - (solvent) based paints

folpet
chlorathalonil
3-iodo-2-propynylbutyl carbamate pentachlorophenol
barium metaborate
trans-1,2 bis (propylsulfonyl) ethene
2,3,5,6 tetrachloro-4-methylsulfonyl pyridine
tribulytin salicylate
thiabendazole
2-n-octyl-4-isothiazolin-3-one

Plastics

folpet
10, 10' oxybisphenoxyarsine
copper-8-quinolinolate
diphenylstibine 2-ethylhexoate
2-n-octyl-4-isothiazolin-3-one
4-chloro-3,5-xylenol
2,3,5,6-tetrachloro-4-methylsulfonyl-pyridine
tributytin monopropylene glycol maleate
tripropytin methacrylate

Wallpaper Flour Adhesive

sodium  o-phenylphenate tetrahydrate
1_(3-chloroallyl)  3,5,7-triaza-l-azoniaadamatane chloride
sodium  pentachlorophenate
6-acetoxy- 2,4-dimethyl-m-dioxane
thiabendazole
chlorathalonil

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      IV.  REGULATORY OPTIONS AND RISK BENEFIT ANALYSIS

A.  INTRODUCTION

     As previously explained, FIFRA requires the Agency to
weigh the risks against the benefits for each use of a pesticide
in order to determine whether continued registration would
cause unreasonable adverse effects on the environment.  In
Chapters II and III, the risks posed by exposure to captan
and the benefits derived from its registered uses were discussed.
To determine whether continued registration of captan is
appropriate, the Agency has identified a number of regulatory
options, and has evaluated each option for its impacts on
both risks and benefits.

     In addition, the Agency has identified registered alter-
native pesticides for the various uses of captan.  The general
risks of alternative pesticides have been summarized based on
the available data.

     This section identifies the regulatory options available
to the Agency to reduce the risks from the registered uses of
captan.  Each option has been evaluated for its impact on the
risks and benefits of the registered uses of captan and the
most appropriate regulatory options have been proposed.

B.  RISK CONCLUSIONS

     Exposure to captan can occur through application of the
pesticide to agricultural crops, harvesting the crops, and
eating foods containing residues of captan.  Exposure can
also occur from non-agricultural application of the pesticide
(e.g., in paints, textiles) and by handling the end product
to which captan has been added.  In these ways, the entire
U.S. population may be exposed to captan residues from
agricultural and non-agricultural uses.  These exposures and
associated risks were discussed in detail in Sections II.C.
and II.D. of this document.

    1.  Oncogenicity

     As indicated in the Captan PD 1, the 1977 report by NCI
showed a statistically significant dose related increase
in adenocarcinomas and adenomatous polyps in B6C3F1 mice fed
captan in their diet over 96 weeks.  To determine whether the
NCI results were accurate and to determine whether a threshold
might exist for tumor development, Chevron performed a High
Dose Study (HDS) (Chevron, 1981) and a Low Dose Study (LDS)
(Chevron, 1983) which showed that adenocarcinomas developed
in the gastro-intestinal tract in male and female mice.  In
addition, Stauffer Chemical Co. performed a chronic feeding
study in Osborne-Mendel rats (Stauffer, 1982).  The results
showed a statistically significant  increase  in kidney tumors
in male rats.  Using data from the  two mouse studies and the

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                             IV-2

rat study, the Agency calculated the Q±* (potency factor).
This potency factor derived from a linearized multistage risk
model and estimate of exposure were then used to estimate the
upper limit, lifetime probability of excess oncogenic risk to
humans.  The specific risk estimates for oncogenicity were
presented in Sections II.D.3 and II.D.4 and include both
agricultural and non-agricultural risks to workers or users
of end-products treated with captan.

    2.  Mutagenicity

     As previously discussed in Section II.E, captan has been
shown to be mutagenic in in vitro experiments in lower
organisms, but the results were negative in the in vivo heritable
translocation test.  The Agency has concluded that captan is
either non-mutagenic in vivo or possesses such a low mutagenic
capacity in the in vivo assays used for quantitative heritable
mutagenic activity that it is not possible to detect mutagenic
activity.  Although captan may be able to cause somatic
mutational events and may, therefore, have an oncogenic
problem, the risk of heritable mutagenicity for humans is low
or nonexistent and does not warrant further testing at this
time.

    3.  Reproduction

     Sections II.B and II.G presented the Agency's concerns
regarding reproductive effects.  The Agency is concerned that
the theoretical maximum residue concentration (TMRC) is 163%
of the allowable daily intake (ADI); thus, there is an
inadequate margin of safety between the no-observable-effeet-
level (NOEL) for toxic effects in reproduction studies and
levels of captan to which people may be exposed through their
diet.  The TMRC was based on the tolerances; actual residue
concentrations may be lower, but the data are not available
to make such estimates.  When registrants submit the required
additional data on captan residues the Agency will recalculate
the exposure and tolerances will be reassessed.  Until such
data are submitted, however, the Agency will base its regulatory
proposals on tolerances.

     4.  Teratology

     Section II.B presented information on teratogenic/feto-
toxic effects of captan.  Laboratory animals exhibited feto-
toxic effects such as reduction in fetal weight and decrease
in number of viable fetuses as well as teratogenic effects
(e.g.,- exencephaly, fused ribs, and microphthalmia) .  Thus,
captan may have the ability to produce fetal abnormalities.
However, the risk assessment indicated that dietary exposure
does not present a risk of concern (because the lowest margin
of safety is 828).  The Margins of Safety were calculated from
a NOEL derived  from a study in hamsters by Robens  (1970),
Because of omissions and/or inconsistencies in tabular data

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                             IV-3

and because statistical analyses were not performed in this
study, the Agency  is requiring registrants to perform another
teratology study in hamsters to evaluate these effects more
definitively.

    5.  Metabolism

     The Agency is concerned about THPI, a plant and animal
metabolite of captan, because this might cause tumors in
laboratory animals.  Current tolerances do not include THPI
and therefore the dietary exposure may be understated.
Therefore, since the Agency does not have sufficient 'data on
residues of THPI to perform a risk assessment, such data will
be requested pursuant to FIFRA 3(c)(2)(B).  When data are
submitted, the tolerances will be reassessed.

    6.  Ecological Effects

     Although captan is acutely toxic to fish, the Agency
does not expect use of captan to cause toxic effects in
non-target aquatic species.  There are no aquatic uses for
captan and no significant leaching or runoff is expected.
Captan is relatively non-toxic to birds and should pose no
hazard to honeybees or predaceous mites.  Thus, captan does
not meet the Agency's risk criteria for ecological effects.

    7.  Risks From Chemical Alternatives to Captan

     The chemical alternatives to captan were listed in
Section III (Benefits Analysis) of this document.  The Agency
has information on the oncogenicity, mutagenicity, reproductive
effects, and teratogenicity/fetotoxic effects for many of
these chemicals.  Table 1 summarizes these effects.  For many
of the chemicals the data base is incomplete.  Without a
complete data base, it is not possible at the present time to
judge the relative toxicities of the alternatives as compared
to captan.  These data wirll be obtained as part of the Agency's
Registration Standards process.

     As indicated in Table 1, the Agency has initiated or
completed Special Reviews and Registration Standards on a
number of the alternative fungicides, and is also planning
on examining the others in the future.  As a result of these
reviews,  the Agency has made regulatory decisions on a number
of fungicides.  In cases where there were potential unreasonable
adverse effects, the Agency took actions to reduce risks;
where data were invalid or lacking, the Agency has required
additional data pursuant to FIFRA 3(c)(2)(B).  As these data
are received and evaluated, the Agency will be better able to
make regulatory decisions on each of the fungicides.

     Table 2 compares the ecological effects for aquatic and
avian toxicity of captan with that of the chemical alter-
natives.  The toxic effects associated with exposure of

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                                         IV- 4

          Table 1 - Summary of Effects of Captan Alternatives
FUNGICIDE
                     ONCO  TERATO  REPPO  MUTA  REGULATORY STATUS
benomyl               +
biphenyl              ?
captafol              +
chlorothalonil        +
coppers               ?
dichlone              ?
dichloran
dinocap               ?
dinoseb               ?
fenarimol             +
ferbam                ?
folpet                I/
mancozeb              +
maneb                 +
metalaxyl             ?
methyl chloroform     ?
methylene chloride    ?
metiram               +
o-phenylphenol        +
sodium arsenite       ?
sodium dimethyl-
  dithiocarbamate     ?
sodium phenylphenate  +
tetraiodoethylene     ?
thiabendazole
thiophenate-methyl    ?
thiram                ?
triadimefon           ?
triforine
triphenytin-hydroxide ?
2-aminobutane         ?
vinclozolin           ?
z ineb                 +
                              p
                              •?
                                     p
                                     7
                                     p
                                     •?
                                     p
                                     •?
p
•p
                                           p
                                           •?
     SR completed 10/82, RS - FY 86

     SR started 12/84
     RS completed 1/81

     RS completed 1/81

     SR started 1/85
     SR cotpleted 10/82, RS - FY 86
     SR completed 10/82, RS - FY 86
     RS completed 8/81
     SR completed 10/82,  RS - FY 86
     DCI sent cut 10/84
SR completed 10/82, RS - FY 85
                                                SR completed  10/82, RS - FY 86
+ = positive effects
- = no effects
? = data gap or not known at this time
SR = Special Review (REAR)
RS = Registration Standard
DCI = Data Call-in Letter
I/ Oncogenic risk assessment in progress

-------
                                IV-5
         Table 2  - Summary of Ecological Effects of Captan
                          Alternatives
Alternative

2-aminobutane

Sodium arsenate

Dichloran

Ferbam

Methyl chloroform

Triforine

Methylene chloride

Tetraiodoethylene

Triadimefon

Vinclozolin

Triphenylt in-hydroxide

Thiophanate methyl

Metalaxyl

Fenarimol
Aquatic Toxicity
                               ND

                               ND
= equal toxicity relative to captan
> greater  "        "      "
< less     "        	
                                           Avian Toxicity

                                                 ND
                           ND

                           ND

-------
                             IV-6

aquatic or avian species to alternatives are greater than,
equal to, or less than the toxicity associated with captan.

C.  BENEFIT CONCLUSIONS

     The benefits of captan were assessed in terms of economic
impacts which would result if its uses were cancelled and
users were forced to employ available alternatives.  As
detailed in Section III, should captan use be cancelled,
moderate economic impacts would fall on the ornamental plant
industry due to the loss of captan use on carnations ($6 to
$12.6 million).  Moderate impacts are also anticipated to occur
for apples ($0.9 - $3.3 million), almonds ($1.4 million),
bushberries ($3.5 - $4.0 million), strawberries ($5.9 million),
peaches ($2.3 - $5.0 million), apricots ($0.4 - $0.7 million),
nectarines ($0.7 million), and seed treatments (up to $9.2
million for all seed treatments).  Although the impact would be
moderate to users of treated seed in aggregate, the per acre
impact for seed treatments would be minor.

    Although not quantified, cancellation of home garden
uses could result in an increase in the cost of disease
control since several more expensive fungicides would be used
to replace the various home garden uses of captan.

     For all other uses of captan, the impacts would be minor
to insignificant for growers and consumers.   The Agency does
not expect any measurable impact on nationwide production or
prices of food, or any other facet of the agricultural economy-

     Registered alternatives exist for almost all uses of
captan but in many cases the alternatives are not as effective.
For the carnation plant industry it was predicted that
resistance would build within two years to the available
alternatives,

D.  DEVELOPMENT OF REGULATORY OPTIONS

     There are three basic options for regulating all pesticides

   Option 1 - Continuation of Registration without Changes

   Option 2 - Continuation of Registration with Modifications
              to the Terms and Conditions of Registration

   Option 3 - Cancellation of Registration

     The two extreme options, Option 1, Continuation of
Registration without Change and Option 3, Cancellation of
Registration, are at the opposite ends of the risk/benefit
spectrum.  Adoption of Option 1 would be appropriate when the
Agency has concluded that the level of risk is acceptable in
light of the pesticide's benefits and that further risk
reduction measures are not necessary to assure that the use

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                             IV-7

of the pesticide meets the statutory standard for continued
registration.

     Adoption of Option 3, cancellation, would be appropriate
when the Agency has concluded that the risks from a use
outweigh the benefits of that use, and that these risks cannot
be mitigated to an acceptable level, in light of the benefits,
by any other measures short of cancellation.  Cancellation
may affect all uses of a compound, only specific uses or
specific formulations, or specific application methods.

     Option 2 is appropriate when the risks of a pesticide
use can be reduced to a level where the benefits of use
outweigh the risks.  This risk reduction is accomplished by
modifying the terms and conditions of the pesticide's registration,
These modifications, which are expressed through the pesticide's
labeling are, for the most part, changes in the way the
pesticide is used.  These changes are designed to reduce
exposure to the pesticide and thereby reduce or eliminate
the risk from the pesticide.  Risk reduction measures were
considered and evaluated for their potential effectiveness and
feasibility.

    1.  Measures to Reduce Dietary Exposure

     Amounts of pesticide residues on food crops are affected
by quantity of active ingredient used, the solvents used for
dilution, mode and schedule of application, preharvest
interval, and soil and weather conditions.  Several measures
were considered as means by which dietary exposure to captan
through residues on food crops might be reduced.

        a.  Preharvest Intervals

     Dietary exposure due to captan residues on food crops might
be reduced if preharvest intervals were extended.  The preharvest
interval is the number of days that must elapse between the
final application of the fungicide and actual harvest.
Lengthening this interval may allow time for dissipation of
residues before crops are harvested.  Additionally, lengthening
the preharvest interval can serve as a means of lowering
tolerances.  However, extending the preharvest interval
cannot be evaluated in the absence of dietary exposure/residue
data that would enable the Agency to determine the extent to
which dietary exposure might be reduced.  Until the necessary
data become available, an informed risk/benefit analysis of
this particular option is not possible.

        b.  Modify Application Practices

     There is the possibility that dietary exposure due to
captan residues on food crops could be reduced if current

application practices were modified.  Specifically, three
possibilities have been considered:  (1) reducing the  amount

-------
                             IV-8

of active ingredient in the formulations, (2) reducing the
amount of formulation applied per season, and (3) reducing the
amount of active ingredient applied per acre.  These modified
application practices, like increasing the preharvest intervals,
might enable tolerances to be lowered. There is also the
possibility that prohibiting post-harvest application could
reduce the captan residues, but since the tolerances estab-
lished do not distinguish between pre- and post-harvest
residues, the Agency cannot determine the extent of risk
reduction if post-harvest applications were prohibited.

     At this time, modified application practices cannot be
pursued as a viable option in the absence of dietary exposure/
residue data that would enable the Agency to determine the
extent to which dietary exposure might be reduced.  Until the
necessary data become available, an informed risk/benefit
analysis of this particular option is not possible.

        c.  Reassess Tolerances for Captan Residues

     The Agency's risk assessment for captan focused primarily
on dietary exposure to captan as a result of various food and
feed uses of captan.  For purposes of calculating worst-case
dietary risk, the Agency assumed that captan residues are
present at current tolerance levels.  Worst-case dietary
exposure could possibly be reduced if captan tolerances were
reassessed and lowered.

     However, the data base to support captan tolerances
is not complete.  Accordingly, the Agency is requiring residue
data pursuant to FIFRA 3(c)(2)(B).  After the required data
are received and evaluated, the tolerances can be reassessed.
However, until the necessary tolerance/dietary exposure data
become available, the Agency will use the worst-case dietary
risk estimates as a basis to propose regulatory action.

        d.  Cancel Food Crops with Highest Dietary Exposure

     An option to cancel only the highest risk food crop uses
(i.e., crops with oncogenicity risks of 10~4 to 10~5 (B2))
was also examined.  However, this option would reduce total
dietary risks by less than an order of magnitude.  The risks
would still be of the order of 10~4 (B2).  This dietary risk
is considered to be too high in light of the moderate to minor
benefits to food crops.

    2.  Measures to Reduce Exposure to Applicators,
        Mixer/Loaders, and Fieldworkers

     The potential risks to person mixing or loading captan
formulations, applying the pesticide to crops, and working in
the fields treated with the pesticide were calculated.  The
specific risk reduction measures which the Agency has considered
are:

-------
                             IV-9

        a.  Protective Clothing

     Dermal and  inhalation exposure to captan can occur during
mixing, loading, maintenance of application equipment, during
application, and at  the time fieldworkers enter treated fields
to weed and harvest.

     Protective  clothing, comprised of gloves and dust masks,
is expected to reduce risk by 80%.  Respirators are expected
to reduce  inhalation exposure by 90%.  If implemented, protective
clothing or equipment requirements would have a minimal
impact on  economic benefits.

        b. Reentry Interval

     Establishing a  reentry interval would allow time for
further breakdown of captan residues.  Presently workers
may reenter fields when the formulation applied to crops has
dried.  However, the Agency has no data on deterioration of
captan or  THPI over  time and thus cannot propose a specific
reentry interval.

     3.    Measures to Reduce End-Use Exposure

     The potential risks to persons using end-use products
(e.g., plastics, adhesives, paints, etc.) containing captan
may be reduced by modification to the concentration used and
by use of  protective clothing.  The risks to people in nursing
homes and  hospitals  using mattresses and pillows containing
captan as  a preservative is reduced by the normal practice of
using sheets and pillow cases or other coverings.

        a. Modification of Concentration

     The risks to users of products containing captan may be
reduced by decreasing the amount of active ingredient in the
mixture.   It is possible that reducing the amount of captan
in plastics, adhesives, paints, cosmetics, and shampoos might
not significantly alter its efficacy, but would decrease
risks.  However, the Agency has no data on which to propose
any reduction in concentration.

        b.  Protective Clothing

     If protective gloves are worn for certain uses of end-
products,  the risk is expected to be reduced by 80%.  If
implemented, a protective glove requirement would have minimal
impacts on economic benefits.  When coverings are used for
mattresses and pillows, the risk is reduced significantly.

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                             IV-10

E.  RISK/BENEFIT ANALYSIS OF REGULATORY OPTIONS

    1.  Agricultural Uses

        a.  Foliar and Post-Harvest Use

     If the registrations of captan products for use on food
and feed crops were continued without restriction (Option 1),
the total dietary cancer risk would be estimated to be 10~3
to 10~4 (B2).  The benefits (estimated to be at $12 to $31
million) would remain unaffected.  The estimated total risk
was based on the TMRC in the absence of residue data to the
contrary.  It was calculated assuming an individual consumed
a normal diet containing food items treated with captan.

     The Agency assumed that captan is present on food crops
at the level of existing tolerances because it is the level
which could legally be present and because the existing
residue data are inadequate for risk assessment purposes.
The residues are probably not as high as the tolerance level,
but they are probably higher than the residues shown for the
selected crops analyzed in the Market Basket Surveys as shown
shown in Section Il.C.l.d. of this document.  Therefore, in
the absence of adequate residue data, the Agency will base
its regulatory proposal for agricultural uses of captan on
dietary risks estimated from exposures based on tolerances.

     Because of lack of data, the Agency does not know
whether amending the terms and conditions of registration
(Option 2) by extending the pre-harvest interval, modifying
the application practices, or reducing the tolerances on crops
would reduce the total dietary risk to any significant extent.

     If the registrations of captan products for food uses
were cancelled (Option 3), all risks to persons consuming
captan treated crops would be eliminated.  The cancellation
of these registrations would have a $12 to $31 million impact.
However, these impacts are considered to be moderate to minor
because these costs are expected to be reasonably absorbed by
growers and consumers; moreover, these costs are low in
relation to the total value of each affected crop.

     Based on the significant cancer risks and moderate to
minor benefits associated with the food uses of captan, the
Agency has determined that the risks outweigh the benefits
for Options 1 and 2.  There is a possibility that actual
residues consumed may be substantially lower than tolerance
levels, and the Agency is requiring data to refine the risk
assessment.  These data include residues on processed crops
found before and after washing, after peeling, and after
processing or cooking.  Data on THPI residues will also be
required.  Validation data for the analytical methodology
used by the registrants for the market basket survey will be
required.  Poultry and cattle feeding studies will be required

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                             IV-11

because residues for milk, eggs, and tissues are lacking.
Residue data for food crops will be required for captan as
well as THPI.  Residue data for captan and THPI is required
in plants which have developed from seeds previously treated
with captan.  The data which are needed for regulatory decision
making will be submitted by the registrants and reviewed by
the Agency before Position Document 4 is issued.  The Agency
encourages all interested parties to submit data on ways in
which exposure to captan might be reduced so that the Agency
will be able to consider all possible risk reduction methods
before making a final regulatory decision in the Position
Document 4.

     In the final decision, the Agency will retain any
use where data are submitted that demonstrate that actual
residues are sufficiently lower than current tolerances or
that modifications to application practices will sufficiently
reduce dietary risk.  However, until the data are submitted,
the Agency proposes to cancel the use of captan products for
use on all food crops in order to eliminate unreasonable
adverse effects from exposure to captan through the diet.
The projected economic impact could be up to $31 million
based on yield losses and increased cost of alternatives.

        b.  Seed Treatment Uses

     Captan was registered for use on seeds as a non-food use
and residue data were not required.  The Agency now considers
seed treatment to be a food use and to continue this use the
Agency will require submission of data to establish tolerances
for the plants which grow from the seeds and which, therefore,
may contain residues of captan and/or its metabolites,
Although the Agency does not have these data, it is assuming,
for the present, that residues resulting from this use would
be present at or below limits of detection, and that the
dietary risks to humans would be insignificant.  Seed treatment
uses will be retained until the required data are submitted
and evaluated to determine whether there are any risks of
concern from this use.

        c.  Detreated Seed Use

     A tolerance was established for detreated corn seed fed
to cattle and hogs on November 6, 1981 (21 CFR 561.65).  The
Agency determined that alkaline washing or roasting of the
treated seeds would decrease the captan residues below 100
ppm.  Feeding studies showed that there would be no captan
residues in these animals if a 14-day pre-slaughter interval
were adopted.  Therefore, based on the benefits and negligible
human dietary exposure, the Agency has decided to continue to
allow feeding of detreated seed corn to cattle and hogs  14
days before slaughter if the residues are less than 100 ppm.

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                            IV-12

    2.  Non-Food Uses (Ornamentals)

        a.  Applicators

     The potential oncogenic risk to persons applying captan
to non-food crops was estimated to be in the range of 10~5 to
10~6  (B2).  The Agency has concluded that these risks must be
reduced by modifying the terms and conditions of registration.
Therefore, the Agency proposes that labels be amended to require
applicators to wear impermeable gloves and dust masks when
applying captan to non-food crops (e.g., ornamentals).  The risks
to these workers would be lowered by 80% to about 10~6 (B2).

        b.  Mixer/Loaders

     If the labels for captan formulations did not contain
further warnings for mixer/loaders (Option 1), the risk to
these workers range from 10~5 to 10~6 (B2).   The Agency has
found that these risks do not warrant cancellation,  but
believes that the risks must be reduced by modifying the
terms and conditions of registration.  The Agency proposes
that the labels be amended to include a requirement that
these workers must wear dust masks and impermeable gloves
when mixing or loading captan formulations.   This would
reduce total exposure by 80%, thus reducing the risk to
about 10~6 (B2).

        c.  Fieldworkers

     Exposure estimates developed for fieldworkers (surrogate
data from harvesters and weedpickers in strawberry fields)
indicate that there is significant dermal exposure to these
workers.  Under Option 1, no restrictions, the risks range
from 10~4 to 10~6 (B2).  These risks would be representative for
all workers in fields or nurseries with ornamentals treated
with captan formulations.  The Agency has found that these
risks are not high enough to warrant cancellation (Option 3),
but believes that the risks must be reduced by modifying the
terms and conditions of registration.  The Agency proposes
that the labels be amended to include a requirement that
these workers must wear water resistant gloves such as leather
or other synthetic materials when working in fields or in
nurseries in which the ornamentals have been treated with
captan formulations.  The risks to these workers would then
be lowered by 90% to an upper limit of 10~6  (B2).

    3.  Non-Agricultural Uses

        a. Applicators

     The potential oncogenic risks to persons incorporating
captan into plastics, adhesives, paints, and cosmetics were
calculated.   The risks were considered negligible for applicators
of captan to plastics, paints, and cosmetics as long as they

-------
                            IV-13

wear protective clothing and a respirator or dust masks (cosmetics)
The upper bound estimates of risks to applicators for adhesives
were 10~5 (B2).  Because these risks may be reduced significantly
(by 80% to 90%) by wearing protective clothing or equipment, the
Agency proposes that applicators wear gloves, protective
clothing, and  respirators (dust masks for cosmetic applicators)
at all phases  of the application process for all non-agricultural
uses.

        b.  End-Uses

     The potential oncogenic risk to users of end products
containing captan were calculated.

            1)  Plastics

     For exposure to plastics containing captan, the risks
were calculated to be negligible.  For exposure to mattresses
and pillows containing captan the upper bound estimate of
risk is 10~5 to 10~6 (B2).  However, the Agency will not propose
any regulatory action for this use since coverings over the
captan-treated mattresses and pillows are used as a normal
practice and are assumed to reduce risk by at least an order
of magnitude to a range of 10~6 to 10~7 (B2).

            2)  Adhesives

     For exposure to adhesives containing captan used in the
home, the upper bound estimates of risks were calculated to
be 10~6 to 10~7 (B2).  For professional use the risk was calculated
to be 10~5 (B2).  These risks are considered by the Agency to
be outweighed  by the benefits of use of captan.  Thus, the
Agency does not propose to take any regulatory action to
modify the terms and conditions of registration of adhesive
products containing captan.

            3)  Paints

     For exposure to paints containing captan, the upper bound
estimates of potential oncogenic risks to users were calculated
to be 10~5 (B2) for oil-based paints and 10~6 (B2) for water-based
paints.  The Agency has found that these risks are not high
enough to warrant cancellation, but believes the risks can be
reduced by modifying the terms and conditions of registration.
The Agency proposes that labels be amended to include a
requirement that impermeable gloves must be worn when applying
oil-based paints for home or professional use.  This would
reduce risks by 80%, thus reducing the risks to levels where
they are outweighed by the benefits.

            4)  Shampoos

     For dog and cat shampoos or powders containing captan, the
upper bound estimate of risk to humans is 10~4 to 10~5 (B2) for

-------
                            IV-14

exposure due to washing pets.  Since there are no registered
alternatives for this use, the Agency concludes that the
benefits outweigh the risks of these uses but only if impermeable
gloves are worn during exposure.  The use of impermeable gloves
will reduce the upper bound estimate of risk by an order of
magnitude to a range of 10~5 to 10~6 (B2).

     For use of the sanitizing deodorant powdered hand soap
containing 0.87% captan (Vancide 89) as an antimicrobial
agent, the upper bound estimate of human potential oncogenic
risk is 10"^ to 10~6 (B2).  This figure is based on a worst-case
exposure scenario; the Agency expects the actual risks to be
lower because the hands are rinsed off right away.  In addition,
because numerous bacteria and fungi may degrade the product
and because the presence of pathogenic bacteria could lead to
infections, the Agency concludes that the benefits of this
minor use of captan outweigh the risks and will not propose
any regulatory action.

            5)  Other End-Use Products

     For exposure to surface sprays and pet powders containing
captan, the upper bound estimates of risks to humans are 10~9
(B2) and 10~8 (B2), respectively.  The risks from exposure to
packing boxes containing captan is assumed to be negligible.
The Agency concludes that the benefits of use outweigh the
risks in these situations and will not propose any regulatory
action.

F.  SUMMARY OF PROPOSED DECISION

    1.  Agricultural Uses

        a.  Foliar and Post-Harvest Use

     Propose to cancel the use of captan products for the
use on all food crops, but require additional residue data
to support tolerances and to determine actual food residues.
However, in the final decision, the Agency will retain any
use where data are submitted that demonstrate that actual
residues are sufficiently lower than current tolerances or
that modifications to application practices will sufficiently
reduce dietary risk.

        b.  Seed Treatment Uses

     Seed treatment uses will be retained until additional
data are submitted to enable the Agency to assess the risks.

        c.  Detreated Seed Use

     Continue the use of detreated seed for feeding to cattle
and hogs.

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                            IV-15

    2.  Non-Food Uses  (Ornamentals)

        a.  Foliar and Post-Harvest Use

     Continue the use of captan products on non-food crops.

        b.  Applicators

     Labels must be amended to include a requirement that workers
must wear impermeable gloves and dust masks when applying
captan formulations.

        c.  Mixer/Loaders

     Labels must be amended to include a requirement that
workers wear dust masks and impermeable gloves when mixing
or loading captan formulations.

        d.  Fieldworkers

     Labels must be amended to include a requirement that
workers wear water-resistant gloves (such as leather or synthetic
materials) when working in fields or nurseries in which the
crops had been treated with captan formulations.  This regulatory
proposal applies only to non-food items such as ornamentals
since the Agency is proposing to cancel registrations of
captan for use on food crops.

    3.  Non-Agricultural Uses

        a.  Adhesives

            1)  Applicators

     Labels must be amended to include a requirement that
workers wear respirators, gloves, and protective clothing
(such as long-sleeved shirts and trousers) at all phases of
the application process, as is the usual industrial practice.

            2)  End-uses

     No proposed action.

        b.  Plastics/Fabrics

            1)  Applicators

     Labels must be amended to include a requirement that
workers wear gloves, protective clothing (such as long-sleeved
shirts and trousers), and respirators at all phases of the
application process, as is the usual industrial practice.

-------
                            IV-16

            2)  End-uses

     No proposed action.

        c.  Paints

            1)  Applicators

     Labels must be amended to include a requirement that
workers wear gloves, protective clothing (such as long-sleeved
shirts and trousers), and respirators at all phases of the
application process, as is the usual industrial practice.

            2)  End-uses

     Labels must be amended to include a requirement that
impermeable gloves be worn when applying oil-based paints
for home or professional use.

        d.  Cosmetics (including animal shampoos and dusts)

            1)  Applicators

     Labels must be amended to include a requirement that
workers wear gloves, dust masks and protective clothing
(such as long-sleeved shirts and trousers)  at all phases of
the application process, as is the usual industrial practice.

            2)  End-uses

     Labels be amended to include a requirement that people
must wear impermeable gloves when washing their pets with
animal shampoos containing captan.  No regulatory will be
proposed for powdered hand soaps, surface sprays, or pet
powders containing captan.

     The Agency will transmit to the FDA for their evaluation
exposure and risk data on other cosmetic uses of captan not
regulated by the EPA.

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Ahmed, F.E., Hart, R.W.; and Lewis, N.J.  1977.   Pesticide
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Anderson, R.F., and Allison, J.R. 1983.  Preliminary Benefit
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Bionetics Research Laboratories, 1968.  Evaluation of the
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Buselmaier, V.W.; Rohrborn, G.; and Propping, P- 1972.
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   Assay and Dominant Lethal Test  in Mice.  Boil Zentralbl
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Canada.  Department  of  Health and Welfare,  1979.  Canadian-U.S.
   Audits of IBT Studies Nos. J5438, M5519, P5387,  and P5398.

Carlton, W.W. 1981.   Bioassay of  Captan Evaluation  of Selected
   Tissue  for Neoplasms.  U.S. National Cancer  Institute Study
   for Stauffer Chemical Co.

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Chevron Chemical Co. 1978.  Captan Residues Found in Market
   Basket Surveys, dated June 5, 1978.

Chevron Chemical Co. 1978.  A 28-Day Feeding Study of Technical
   Phaltan in Mice.  EPA Assession Nos.  249485 - 95.

Chevron Chemical Co. 1981.  Lifetime Oncogenic Feeding Study
   of Captan Technical (SC-944)  in CD-I  Mice (ICR Derived).
   EPA Accession Nos. 244220 - 26.

Chevron Chemical Co. 1981.  Teratology Study in Rabbits.   EPA
   Accession No. 246624.

Chevron Chemical Co. 1982.  Lifetime Oncogenic Feeding Study of
   Diofolatan Technical in Mice.  EPA Accession Nos. 248209 - 17.

Chevron Chemical Co. 1982.  Lifetime Oncogenic Feeding Study of
   Phaltan Technical (SX-946) in CD-I (ICR Derived)  Mice.   EPA
   Assession Nos. 249485 - 95.

Collins, T.F.X. 1972a.  Dominant Lethal  Assay.  I. Captan.
   Food and Cosmetic Toxicol. 10s  353-61.

Collins, T.F.X. 1972b.  Effect of Captan and Triethylenemelamine
   (TEM) on Reproductive Fitness of DBA/2J Mice.   Toxicol. and
   Appl. Pharmacol. 23: 277-87.

Couch, R.C.? Siegel, M.R.; and Dorough,  H.W.,  1977.   Fate  of
   Captan and Folpet in Rats and Their Effection on Isolated
   Liver Nuclei.  Pest. Biochem. Physiol.  7: 547-58.

Courtney, K.D.; Andrews, J.E.;*and Stevens,  T.J.  1978.  Ihalation
   Teratology Studies with Captan and Folpet.   Toxiocol. and
   Appl. Pharmacol. 45: 292.

Cox,  D.R. 1972.  Regression Models and Life Tables (with
   discussion).  J. of Royal Statist. Soc. B34:  187-220.

Croft, B.A., and Nelson, E.E. 1972.  Toxicity of Apple Orchard
   Pesticides to Michigan Polulations of Amblyseius Fallacis.
   Enviro. Entomol. 1: 576-79.

Daines, R.H.j Lukens, R.J.; Brennan, E.; and Leone,  I.A. 1957.
   Phytotoxicity of Captan as Influenced by Formulation,
   Environment, and Plant Factors.  Phytopathology 47: 567-73.

Dalvi, R.R., and Ashley, W.M. 1979.  Protective Effects of
   Glutathione on the In Vitro Inhibition of Hepatic Cytochrome
   P-450 by Captan.

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                            - 3 -

Day, H.R. 1982.  Estimating Pesticide Exposure from Airblast
   Application.  Paper presented at the 1982 Annual Meeting of
   the Toxicology Forum, July 19-23,  at the Given Institute of
   Pathobiology, Aspen, Colorado.

Day, H.R. 1984a.  Memorandum to Ester Saito, EPA, Washington,
   D.C., entitled Revised and Supplemented Captan Exposure
   Assessment, dated October 9, 1984.

Day, H.R. 1984b.  Memorandum to Carol Langley, EPA, Washington,
   D.C., entitled Non-Agricultural Uses of Captan, dated
   December 14, 1984.

Day, H.R. 1984c.  Memorandum to Lois Rossi, EPA,  Washington,
   D.C., regarding Exposure Assessment for Pentacholorophenol
   (Non-Wood), dated May 17, 1984.

Day, H.R. 1985.  Memorandum to Jeff Kempter, EPA, Washington,
   D.C., concerning Captan Exposure (Flower Production),  dated
   March 6, 1985.

DeBaun, J.R.; Miaullis, J.B.; Knarr,  J.; Mihailovski,  A.?  and
   Menn, J.J. 1974.  The Fate of N-trichloro-14C-methyl-thio-
   4-cyclohexene-l,2-dicarboximide (14C-Captan).   Xenobiotica
   4: 101-19.

Deer, H. 1981.  Dermal and Inhalation Exposure to Commercial
   Apple Growers to the RPAR Pesticide Captan.  Submitted  for
   publication in the American Industrial Hygiene Association
   Quarterly.

Devine, K. 1983.  Preliminary Benefit Analysis of Captan  Use on
   Cherries.  Office of Pesticide Programs, EPA,  Washington, D.C,

Drake, C.; Lawrence, E.; and Singleton, F. 1981.   Biology  of
   Major Apple Diseases and Their Control with Captan  and
   Alternatives - Draft Analysis.  Virginia Polytechnic
   Institute and State University, Blacksburg.

Earl, F.L.; Miller, E.; and Van Loon, E.J. 1973.   Reproductive
   Teratogenic and Neonatal Effects of Some Pesticides and
   Related Compounds in Beagle Dogs and Miniature Swine.   Paper
   read at 8th Inter-Amer. Conf. Tox. Occu. Med.

Engst, R., and Rabb, M. 1973.  On the Metabolism of Fungicidal
   Phtalimide Derivatives from the Food-chemistry Toxicological
   View.  Nahrung 17: 731-38 (translated from German).

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                            _ 4 -

Epstein, S.S.; Arnold, E.; Andrea, J.; Bass,  W.;  and Bishop,
   Y. 1972.  Detection of Chemical Mutagens by the Dominant
   Lethal Assay in the Mouse.  Toxicol and Appl.  Pharmacol.
   23: 288-325.

Everhart, L.P., and Holt, R.F. 1982.   Potential Benlate Fungicide
   Exposure during Mixer/loader Operations, Crop Harvest,  and
   Home Use.  J. Agric. Food Chemistry 30:  222.

Fabro, S.; Smith, R.L.; and Williams,  R.T.  1966.   Embryotoxic
   Activity of Some Pesticides and Drugs Related to Phtahlimide.
   Food Cosmet. Toxicol. 3: 587-90.

Faller, G.; Hornick, F.; Norton, V.;  and Wichelns, D. 1981.
   An Analysis of the Potential Economic Effects of the
   Cancellation of Captan for Use in Controlling Turfgrass
   Diseases.  University of Maryland,  College Park.

Ficsor, G; Bordas, S.; Wade, S.M.; Muthiani,  E.;  Wertz, G.F.?
   and Zimmer, D.M. 1977.  Mammlian Host and Fluid-Mediated
   Mutagenicity Assays of Captan and Stretozotocin in
   Salmonella Typhiumurium.  Mutation Research 48: 1-16.

Fry, S.M., and Ficsor, G. 1980.  Cytogenetic Test of Captan
   in Mouse Bone Marrow.  Mutation Research 58: 111-14.

Gait, D; Pierce, B; Hughett, N.; and Fenton,  R. 1983.  The
   Biologic and Economic Assessment of Captan Use on Eight
   California Commodities:  Almond, Apricot,  Grape, Nectarine,
   Clingstone Peach, Freestone Peach,  Plum, and Prune - Draft
   Analysis.  University of California, Davis.

Gehan, E.A. 1975.  Analysis of Survival Data Under the Pro-
   portional Hazards Model.  Int. Stat. Rev.  43:  45-58.

Generoso, W.M.; Bishop, J.B.; Gosslee, D.G.;  Hewell, G.W.;
   Sheu, C.J.; and von Halle, E. 1980.  Heritable Translo-
   cation Test in Mice.  Mutation Research 76: 191-215.

Goldenthal, E.I. 19'78.  Teratology Study in Hamsters.  Inter-
   national Research and Development Corp.   Study peformed
   for Chevron Chemical Co.  EPA Accession No. 249681.

Graham, G. 1981.  Health and Welfare,  Canada.  Memorandum  to
   Stalker, J., Agriculture Canada, concerning Captan Residues
   on Imported Fruit and Vegetables for Projects FM18 and
   FBAO, dated April 13, 1981.

Grube, A.H. 1983.  Preliminary Benefit Analysis of Captan  for
   Seed Treatment of corn, Soybeans,  and Small Grains - Draft
   Analysis..  University of Illinois,  Urbana.

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Gunderson, E. 1982.  Food and Drug Administration.  Memorandum
   to Janice K. Jensen, EPA, Washington, B.C., concerning
   Captan Residues in the Total Diet Studies for FY 75-80 and
   the Printouts of Captan Findings in Various FDA Monitoring
   Programs in FY 78-81, dated January 27, 1982.

Hazelton Laboratories America, Inc. 1983.  Chronic Toxicity
   Study in Rats.  EPA Accession Nos. 250921 - 24.

Hill, E.F.; Health, R.G.; Spann, J.W.; and Williams,  J.D. 1975.
   Lethal Dietary Toxicities of Environmental Pollutants to
   Birds.  U.S. Department of Interior, Fish & Wildlife Service,
   Spec. Sci. Rep. - Wildlife No. 191.

Hoffman, L.J.; DeBaun, J.R.; Knarr, J.; and Mann,  J.J.  1973.
   Metabolism of N-(Trichloromethylthio)-!,2-dicarboximido-
   14C-4-cyclohenzene (Captan) in the Rat and Goat.  Western
   Research Center, Stauffer Chemical Co.

Hoyt, S.C. 1969.  Integrated Chemical Control of Insects and
   Biological Control of Mites on Apples in Washington.
   J. Econ. Entomol. 62: 74-86.

Innes, J.R.M.; Ulland, B.M.; Valerio, M.G.;  Petrucelli, L.;
   Fisbein, L.; Hart, E.R.; Pallota, A.J.; Bates,  R.R.;
   Falk, H.L.; Gart, J.J.; Klein, M.; Mitchell, I.; and
   Peters, J. 1969.  Bioassay of Pesticides and Industrial
   Chemicals for Tumorigenieity in Mice: a Preliminary  Note.
   J. the National Cancer Institute 42: 1101-14.

International Research and Development Corp. 1982.  Three
   Generation Reproduction Study in Rats, submitted by
   Chevron Chemical Co.  EPA Acession No. 249334.

Jacobsen, B.J. 1982.  An Analysis of Current Captan Uses:
   Their Benefits, the Role of Alternatives, Impacts  to
   Agriculture from Changes in Captan Use Patterns and
   Applicator Exposure.  University of Illinois, Urbana.

Jensen,  J.K. 1982.  Memorandum to Carol Langley, EPA,
   Washington, D.C., concerning Captan PD 2/3 Applicator
   Exposure Analysis - Final Report, dated May 21, 1982.

Johnson, W.W., and Finley, M.T. 1980.  Handbook of Acute
   Toxicity of Chemicals to Fish and Aquatic Invertebrates,
   Summaries of Toxicity Tests Conducted at Columbus National
   Fisheries Research Laboratory, 1965-78.  U.S. Department
   of Interior, Fish & Wildlife Service. Resource Pub.  137.

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                            - 6 -

Kennedy, G.L.; Fancher, O.E.; and Calandra, J.C. 1968.  An
   Investigation into the Teratogenic Potential of Captan,
   Folpet, and Difolatan.  Toxicol. and Appl. Pharmacol.
   13: 420-30.

Kennedy, G.L.; Fancher, O.E.; and Calandra, J.C. 1975.
   Nonteratogenicity of Captan in Beagle Dogs.  Teratology
   5: 223-25.

Lacayo, H. 1984a.  Memorandum to Carol Langley, EPA, Washington,
   D.C., concerning Revised Captan PD 2/3 Quantitative Risk
   Assessment, dated October 15, 1984.

Lacayo, H. 1984b.  Memorandum to Carol Langley, EPA, Washington,
   D.C. , concerning Update to Captan Risk Assessment for
   Strawberry Pickers, dated December 17, 1984.

Lagator, M.; Kelly, F.J.; Green, S.; and Oswark, E.J.  1969.
   Mutagenic Effects of Captan.  Ann. N.Y. Acad. Sci. 106:
   344-51.

Lavy, T.L.; Shepard, J.S.; and Mattice, J.D. 1980.  Exposure
   Measurements of Applicators Spraying (2,4,5-Trichlorophenoxy)
   Acetic Acidin in the Forest.  J. Agric. Food Chem. 28:  626-30.

Litton Bionetics, 1980.  Mutagenicity Evaluation of Captan in
   the Somatic Cell Mutation Assay - Final Report.  Submitted
   by Chevron Chemical Co.  EPA Accession No. 251576.

Makhteshim Chemical Works, Ltd. 1983.  Life-Spray Carcinogenicity
   Study of Merpah (Captan) in Rats.  EPA Accession Nos. 252722 -
   32.

Marshall, T.C.? Dorough, H.W.; and Swim, H.E. 1976.  Screening
   of Pesticides for Mutagenic Potential Using Salmonella
   Typhimurium Mutants.  J. Agr. Food Chem. 24: 560-63.

Metcalf, R.L., and Sanborn, J.R. 1975.  Pesticides and
   Environmental Quality in Illinois.  111. Nat. Hist. Survey
   Bull. 31: 381-43'6.

Mitre Corporation,  1981.  Use Profiles, Alternatives Assessment,
   and Exposure Analysis for Captan at Industrial Sites.  EPA
   Contract No. 68-01-5944.

Moriya, M.; Kato, K; and Shirasu, Y. 1978.  Effects of Cysteine
   and a Liver Metabolic Activation System on the Activities
   of Mutagenic Pesticides.  Mutation Research 57: 259-63.

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                             — 7 —

National Cancer Institute, 1977.  Bioassay of Captan for
   Possible Carcinogencity.  Carcinogenesis Technical Report
   Series #15, CAS No. 133-06-2.

Nelson, B.D. 1971a.  Action of the Fungicides Captan and
   Folpet on Rat Liver Mitchondria.  Biochem. Pharmacol.
   20: 737-48.

Nelson, B.D. 19715.  Induction of Mitchonodrial Swelling by
   the Fungicide Captan.  Biochem. Pharmacol. 20:  749-58.

Nelson, E.E.? Croft, B.A.; Howitt, A.J.; and Jones,  A.L.
   1973.  Toxicity of Apple Orchard Pesticides to Agistemus
   Fleschneri.  Enviro. Entomol. 2: 219-22.

Norton, G.; Kuchler, F.; and Baumes, H. 1982.  Economic
   Analysis of Captan Use for Control of Apple Diseases -
   Draft Analysis.  Virginia Polytechnic Institute and

Offutt, C.K. 1984.  Memorandum to Carol Langley, EPA,
   Washington, D.C., entitled Fieldworker Exposure to Captan,
   dated December 21, 1984.

Ofiara, D.; Allison, J.; McMahon, G.; and Elias, B.  1983.
   Preliminary Benefit Analysis of Captan Use on Peaches
   for the Northeastern, Southern, and Midwestern Regions
   of the United States - Draft Analysis.  University of
   Georgia, Experiment.

Peeples, A., and Dalvi, R.R. 1978.  lexicological Studies
   of Captan:  Its Metabolism by Rat Liver Drug-Metabolizing
   Enzyme System.  Toxicology 9: 341-51.
                               te~
Pelletier, E.N. 1982a.  Memorandum to Captan RPAR RM entitled
   Final Use Practices Report Relative  to Application and
   Exposure, dated April 9, 1982.

Pelletier, E.N. 1982b.  Memorandum to Captan RPAR RM entitled
   Use Analysis for Captan Application  Sites, dated January
   28, 1982.

Pelletier, E.N. 1985.  Memorandum  to Captan Review Managers,
   EPA, Washington, D.C., entitled Use  Practice Report for
   Exposure Analysis—Potential Captan  Exposure for Cut Flower
   Production Workers, dated February 12,  1985.

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                            - 8 -

Peto, R.; Pike, M.C.;  Day, N.E.;  Gray,  R,G.;  Lee,  P.M.;
   Parish, S.; Peto, J.; Richards,  S.;  and Wahrendorf, J.  1980.
   Guidelines for Simple, Sensitive,  Significant Tests  for
   Caroginogenic Effects in Long-Term Animal  Experiments.   In
   Monographs;  Long-Term and Short-Term Screening Assays  for
   Carcinogens;  a Critical Appraisal,  Supplement 2,  311-426.
   Geneva:  World Health Organization.

Popendorf, W.J. 1984.   Personal communication,  dated
   December 7, 1984.

Popendorf, W.J.; Leffingwell, J.T.;  McLean, H.R.;  Zweig, G.;
   and Witt, J.M. 1982.  Final Report - Youth in Agriculture—
   Pesticide Exposure to Strawberry  Pickers,  1981  Studies.
   Office of Pesticide Programs,  EPA, Washington,  D.C.

Reinert, J.C. 1985.  Memorandum to Carol Langley,  EPA,
   Washington, D.C., regarding Exposure from  Use of Captan
   in Pet Power, Packing Crates,  and Aerosol  Sprays,  dated
   March 6, 1985.

Reinert, J.C., and Severn, D.J. 1985.  Dermal Exposure  to
   Pesticides:  EPA's Viewpoint.   In Dermal Exposure  Related
   to Pesticide Use;  Discussion of  Rick Assessment,  ed.
   Honeycutt; Zweig; and Ragsdale, pp.  357-68.   Washington:
   American Chemical Society.

Richmond, D.V., and Somers, C. 1968.   Ann.  App.  Biol. 62:  35.

Robens, J.F. 1970.  Teratogenic Activity of Several Phthalimide
   Derivatives in the Golden Hamster.  Toxicol.  and Appl.
   Pharmacol. 16: 24-34.

Rohrborn, G. 1970.  The Dominant Lethals:   Method  and
   Cytogenetic Examination of Early  Cleavage  Stages.  Springer-
   Verlaq (Berlin) 148-55.

Saito, E. 1981.  Memorandum to Carol Langley, EPA, Washhington,
   D.C., entitled Rebuttal Assessment for Captan PD 1, dated
   December 2, 1981.

Saito, E. 1984.  Memorandum to Carol Langley, EPA, Washington,
   D.C., concerning Captan Dietary Risk Assessment, dated
   December 5, 1984.

Saito, E. 1985.  Note to Carol Langley, EPA,  Washington, D.C.
   entitled Risk from Minor Use,  dated March  13, 1985.

Schafer, E.W. 1972.  The Acute Oral  Toxicity  of 369 Pesticidal,
   Pharmaceutical and other Chemicals to Wild Birds.  Toxicol.
   and Appl. Pharmacol. 21: 315-30.

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                            - 9 -

Schneider, W.R. 1982.  Memorandum to Carol Langley,  EPA,
   Washington, D.C., regarding Worst Case Teratology Risk  for
   Captan in Dietary Single Servings, dated February 12, 1982.

Schneider, W.R., and Burnam, W.L. 1984.   Memorandum  to Carol
   Langley, EPA, Washington, D.C.,  regarding Submission of
   Toxicology Section of the PD 2/3 for Captan,  dated
   October 16, 1984.

Seidler, H.; Hartig, H.; Schnaak, W.; and Engst,  R.  1971.
   Untersuchungen uber den Meetabolismus Einiger Insektizide
   und Fungizide in der Ratte.  Die Nahrung 15:  177-85.

Selsky, C.A. 1981.   The Association of Captan with Mouse and
   Rat Deoxyribbonucleic Acid.  Stauffer Chemical Co.  Report
   No. T-10435.

Simmon, V.F.; Mitchel, A.D.; and Jorgenson, T.A.  1977.  Eval-
   uation of Selected Pesticides as Chemical Mutagens:  In
   Vitro and In Vivo Studies.  Stanford Research Institute.
   EPA Contract 68-01-2458.

Staiff, D.C.; Comer, S.W.; and Wolfe, H.R. 1975.  Exposure to
   Herbicide Paraquat.  Bull. Environ. Contain. Toxicol. 14s
   334-40.

Stauffer Chemical Co. 1979.  Captan Residues Found in Market
   Basket Survey, dated June 6, 1979.

Stauffer Chemical Co. 1982a.  Applicator Exposure to Captan
   During Air-Blast Spraying of^Apples:   Preliminary Evaluation
   of Pennsylvania State University Data.  EPA Accession No.
   248429.

Stauffer Chemical Co. 1982b.  Captan 50-WP:  a Dermal
   Absorption Study in Rats.

Stauffer Chemical Co., and Chevron Chemical Co.  1982.   Two Year
    Oral Toxicity/Carcinogenicity Study of Captan in Rats. EPA
    Assession Nos.  249335-38 and 249731.

Stevens, E.R., and Davis, J.E. 1980.  Potential Exposure of
   Workers During Potato Seed Piece Treatment with Captan.
   Bull. Environ. Contain. Toxicol. , in press.

Stevens, R.R. 1982.  EPA evaluation of Risk Analysis of Captan
   for Aquatic and Terrestrial Wildlife in Context with its
   Use Rates and Practices on Apples, Almonds, Strawberries,
   Potatoes, Soybeans, and Home Gardens, dated February 24,
   1982.

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                          - 10 -

Swenberg, J.A.;  Petzold, G.L.j and Harbach, P.R.  1976.   _In
   Vitro DNA Damage/Alkaline Elution Assay for Predicting
   Carginogenic Potential.  Biochemical and Biophysical
   Research Communication 72s  732-38.

Tezuka, H.; Ando, N.; Suzuki,  R.;  Terahata, M.; Moriya, M.,«
   and Shirasu, Y. 1978.  Cytogenetic and Dominant Lethal
   Studies in Captan.  Mutation Research 57: 201-07.

Thomas, D.G.j Breslow, N.; and Gart, J.J. 1977.  Trend and
   Homogeneity Analyses of Proportions and Life Table Data.
   Computers and Biomedical Research 10s  373-81.

Truhaut, R.; Do Phuoc, H.? and Phu Li, N. 1974.  Effect of
   Organohalogenated Pesticides and PCB's on Zoxazolamine
   Metabolism in the Rat.  C.R. Acad. Sci. [D]  (Paris)  278$
   3003-06 (translated from French).

U.S. Department of Agriculture. Agricultural Research Service.
   1977.  Family Food Buying.   Home Economics Research Report
   Number 37-

U.S.  Department of Health, Education, and Welfare,  1969.
   Report of the Secretary's Commission of Pesticides and
   their Relationship to Environmental Health.

U.S. Department of Health and Human Services.  Food  and Drug
   Administration, 1983.  Tolerances for Pesticides  in Animal
   Feeds Administered by the Environmental Protection Agency
   —Captan.  Code of Federal Regulations, Vol. XXI,  §  561.65.

U.S. Department of Health and Human Services.  Public Health
   Service, 1982.  Meeting of the  National Toxicology Program
   Board of Scientific Counselors, September 22,  23,  and 24,
   1982.

U.S. Environmental Protection Agency, 1983.  Criteria for
   Determination of Unreasonable Adverse Effects.   Code of
   Federal Regulations, Vol. XL, § 162.11.

U.S. Environmental Protection Agency, 1984.  Notice.   "Proposed
   Guidelines for Carcinogen Risk  Assessment? Request for
   Comments."  Federal Register, IL, No.  227, November 23,
   1984, 46294-46301.

U.S. Environmental Protection Agency, 1980.  Notice.   "Rebut-
   table Presumption Against Registration (RPAR)  and Continued
   Registration of Pesticide Products Containing  Captan."
   Federal Register, XLVC, No. 161, August 18,  1980,  54938 - 52.

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                            - 11 -

U.S. Environmental Protection Agency, 1984.  Preliminary
   Benefit Analysis of Captan - Draft Analysis.

Urbanek-Karlowska, B. 1977.  The Activity of Microsomal Enzymes
   of Rat Liver in Relation to Dietary Protein Level and the
   Administration of Selected Pesticides.  Rocz. Panstw. Zakl.
   Hig. 28: 243-51 (translated from Polish).

Verrett, W.J.; Mutchler, M.K..; Scott, W. F.; Reynolds, E.F.;
   and McLaughlin, J. 1969,  Teratogenic Effects of Captan
   and Related Compounds in the Developing Chicken Embryos.
   Annals of N.Y. Acad. Sci. 160: 334-43.

VonDruska, J.F.; Fancher, O.E.; and Calandra, J.C. 1971.
   Investigation into the Teratogenic Potential of Captan,
   Difolatan, Folpet in Non-human Primates.  Toxicol.  Appl.
   Pharmacol. 18: 619-24.

Whitson, R., and Daugherty, L.S. 1983.  Preliminary Benefit
   Analysis of Captan Use on Cotton - Draft Analysis.
   University of Arizona, Tucson.

Wichelns, D; Hornick, F.; and Norton, V. 1982.  An Economic
   Analysis of a Potential Cancellation of Captan Fungicide
   for Use in Controlling Diseases Affecting Ornamental Plants
   - Draft Report.  University of Maryland, College Park.

Winterlin, W.L.; Kilgore, W.E.; Mourer, C.R.; and Schoen,  S.R.
   1984.  Worker Reentry Studies for Captan Applied to Straw-
   berries in California.  J. Agric. Food Chem. 32: 664.

Wolfe, H.R.; Durham, W.F.; and Armstrong, J.F. 1967.  Exposure
   of Workers to Pesticides.  Ajrch. Environ. Health 14: 622-33.

Zendzian, R.P. 1982.  Memorandum to Holmer Hall, EPA,  Washington,
   D.C., concerning Captan Dermal Penetration Study, dated
   November 18, 1982.

Zweig, Gunter; Gao, Ru-Yu; and Popendorf, W. 1983.  Simultaneous
   Dermal Exposure to Captan and Benomyl by Strawberry Harvesters,
   J. Agric. Food Chem. 31: 1109.

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