LINDANE POSITION DOCUMENT 4




     Office of!Pesticide Programs



U. S. ENVIRONMENTAL PROTECTION AGENCY




          401 M Street, S.W.




       Washington, D. C. 20460

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                                                       OPTS-TECHNICAL INFORMATION
                          ACKNOWLEDGMENTS
Steven Bayard, Biostatistician,  Carcinogen Assessment Group
Mark Dow, Entomologist,  Animal Sciences and Indexes Branch
Donald Eckerman, Economist,  Economic Analysis Branch
Roger Gardner, Toxicologist, Toxicology Branch
Bernard Hacerman, Pathologist, Carcinogen Assessment Group
Dick Hill, Science Advisor to the Assistant Administrator
Anne Hollander, Project Manager
Janice Jensen, Environmental Fate Branch
Irving Mauer, Geneticist, Toxicology Branch
Robert McGaughy, Acting Director, Carcinogen Assessment Group
Thomas Parshley, Registration Division
Amy Rispin, Science Integration  Staff
Esther Saito, Environmental Fate Branch
Rick Stevens, Ecological Effects Branch
Judith Wheeler, Attorney, Office of General Counsel.
Linda Vlier, Economist,  Economic Analysis Branch

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                             EXECUTIVE  SUMMARY


In July  1980  the  Environmental Protection Agency  issued Lindane Position
Document 2/3  (PD  2/3)  which proposed to cancel most of the uses of the
insecticide lindane  (45  FR 45362).   The proposal  was based on a riskbenefit
determination which  suggested that  the risks considerably outweighed the
benefits associated  with lindane1s  continued use.

This document, Lindane Position Document 4, presents EPA's final determination
on lindane. It is based  on a revised analysis of  the risks and benefits,
following careful consideration of  the comments EPA has received from the
Scientific Advisory  Panel,  the U.S.  Department of Agriculture, members of
the affected  industries,  and the general public.

The decision  described in this document is quite  different from the 1980
proposed decision.   EPA  originally  planned to cancel all of lindane1s uses
except for the commercial ornamental,  livestock,  and dog wash uses.  The
final decision is to continue registration of most uses of lindane.  The
Agency will cancel the indoor uses  of  smoke 'fumigation devices and the use
of dog dips to control pests other  than mites.  All other uses of lindane
will be  continued with various restrictions.  These restrictions vary ac-
cording  to the degree  of hazard associated with the use, but typical require-
ments include protective clothing,  label statements describing necessary
precautions,  and restriction of some uses to certified pesticide applicators.

The many reasons for these  changes  are discussed  in detail in the body of
this document.  However,  there are  five primary considerations which caused
EPA to revise its proposed  decision.

First, the Scientific  Advisory Panel (SAP) disagreed with many of the regulatory
positions proposed in  the PD 2/3.   Because of the position taken by the SAP,
the Agency undertook a thorough reevalution of the analysis and regulatory position
proposed in the PD 2/3.

Second,  the exposure estimates used in the original analysis were purposefully
conservative,  since  they were based on a paucity  of information.  EPA prefers
in such  cases to err on  the side of safety.  Since the proposed decision (PD
2/3) was published,  EPA  has been able  to improve  its risk estimates signifi-
cantly.  Seme of the revisions are  based on new,  more detailed use information,
including the routine  use of protective clothing  for some uses.  Others are
based on the  use of  better  surrogate data.  Details of all the changes in
the exposure  analysis, and  the reasons for them,  may be found in Appendix III.

The third reason for the revised decision is that EPA's assessment of the
possible risks from  lindane,  particularly the potential cancer risks, suggest
that the available information is not  sufficient  to support cancelling the use
of lindane.   This conclusion is based  on a combination of three key consider-
ations:  1) evidence  regarding the magnitude of the potential cancer risk to
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humans is limited; 2) most of the cancer risks (which are conservative estimates)
can be acceptably reduced by less stringent measures than cancellation;
and 3) potential risks to the exposed populations from leaving lindane on
the market while additional testing is done are not estimated to be significant.
Even the possible risks from a working lifetime of exposure, as estimated in
this document, are in most cases adequately low.  Further discussion of the
details of cancer risk considerations, and the Agency's decision on how to
deal with the many uncertainties surrounding this issue, may be found under
"II. A.  The Presumption of Oncogenicity".

Fourth, the Agency has reevaluated the issue of fetotoxic effects, the comments
received on this subject, and the animal studies showing such effects.
Effects on reproduction are of concern to the Agency; however, their toxico-
logical end point must be  considered in relation to other toxicological
effects.  The fetotoxic effects of lindane only occur at exposure levels above
those showing maternal toxicity.  The Agency, therefore, concludes that the
risk reductions discussed in PD-4 (labelling, restriction of use to informed
persons) will concommitantly and sufficiently reduce the risk of fetotoxicity.

Fifth, the notable benefits of lindane1siuse are given more appropriate
consideration in the final decision, as was suggested in the many comments
which the Agency received.  The decision proposed in 1980 was criticized by
the U.S. Department of Agriculture and the public, for not adequately con-
sidering ways to reduce the risks through less stringent measures than
cancellation.  The Agency agrees that the benefits were not adequately
considered in its original assessment, and has revised the risk/benefit
analysis accordingly.

In conclusion, this final decision on the pesticidal uses of lindane is based
upon better information and consideration of the reasonable regulatory options
short of cancellation.  The final decision has been carefully designed to
insure that immediate but minimally burdensome steps will be taken to reduce
the potential risks to exposed populations.  At the same time, this decision
preserves the benefits of lindane1s use while ensuring that uncertainties
surrounding some of the risks will be reduced within a reasonable time frame.

A three month, subchronic oral feeding study in rats recently submitted to  ^
the Agency indicates a NOEL of 0.3 mg/kg/day with kidney damage at the next   I
highest dose.  In order to properly evaluate this study it will be necessary _J
for the Agency to thoroughly review the complete subchronic and chronic data
base, which was not done as part of this RPAR.  The Agency has decided not to
delay the issuance of the PD 4 because it does not want to delay the imple-
mentation of the protections to the environment contained in the regulatory
measures in the PD 4.  However, the Agency will give high priority to the
development of a Registration Standard for lindane which will include a
complete review of lindane1s general toxic effects.
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                                TABLE OF CONTENTS
   I. INTRODUCTION	1
  II. HEALTH and ENVIRONMENTAL CONCERNS: final analysis	5
     A. The presumption of ONCOGENICITY	6
        1.  EPA1 s PD  2/3 position	6
        2.  Comments  on EPA's PD 2/3 position, & PD 4 final position. .6
           a. Choice  of An Appropriate Risk Model	6
           b. Use of  Pooled Controls	10
           c. Tumor Classification	11
           d. IARC Classification of Lindane	11
           e. Alpha-fetoprotein Levels in the Hanada Study	12
           f. Tumor Classification  in the Goto et al. (1973) Study	12
           g. Possible Cross-contamination in the NCI Bioassay	12
           h. EPA's PD 4 Final Position on the Presumption of
              Oncogenicity	13
        3.  Metabolism of Lindane	13
        4. : Mutagenicity;.	,	> . <. .14
        5. ' Bioassays of; Lindane and Its Metabolites in Laboratory'  '
            Animals	16
        6.  Quantitative Risk Assessment of Lindane	20
        7.  Summary	,	20
     B. The Presumption of FETOTOXICITY/REPRODUCTIVE EFFECTS	21
        1. EPA's PD 2/3 Position	21
        2. Comments on EPA*s PD 2/3 Position	21
        3. EPA's PD 4 Final Determination	22
 III. OTHER POSSIBLE  ADVERSE EFFECTS	26
     A. EPA's concern regarding ACUTE and SUBACUTE HAZARDS to humans
        and. domestic  animals	27
        1. EPA's PD 2/3 Position	27
        2. Comments on EPA's PD 2/3 position, and the Agency's
           PD 4 determination	28
           a. Basis for calculating the margin of safety	28
           b. Central nervous system effects	29
           c. Sensitivity of children to lindane	32
     B. Possible association between lindane and BLOOD DYSCRASIAS	34
        1. EPA's PD 2/3 position	34
        2. Comments received	34
        3. EPA's PD 4 Position	34
     C. ACUTE TOXICITY TO AQUATIC WILDLIFE	35
        1. EPA's PD 2/3 position	35
        2. Comments received, and EPA's PD 4 final position	'...35
     'D. Possible POPULATION REDUCTIONS in non-target avian species....36
     E. Possible ISOMERIZATION	36
     F. General Toxicity of Lindane	36
IV.  EXPOSURE: final  determination	38
     A. NON-DIETARY EXPOSURE	39
     B. DIETARY EXPOSURE	44
 V.  BENEFITS: final  determination	49
VI.  SUMMARY OF KEY RISK-BENEFIT CONSIDERATIONS	53
                                   IV

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    A. Cncogenicity: key points	54
    3. Fetotoxicity/reproductive effects: key points	54
    C. Acute hazards to humans and domestic animals: key points	55
    D. Susceptibility of Children	55
    E. Possible association between lindane and blood dyscrasias:
       key points	56
    F. Acute toxicity to aquatic wildlife	56
    G. Key points in the exposure analysis	56
    H. Key points in the benefits analvsis	57
VII.   RISK-BENEFIT ANALYSES 	".	58
    A. General notes	59
    B. Interpreting the quantitative cancer estimates	59
    C. Margin of safety estimates	60
    D. Risk/Benefit Summary Tables	61
    S. Risk-benefit analyses for seven key routes of exposure,
       and use-by-use final determinations	68
       1. Above—shoulder spray applications: air blast or
          power hand gun equipment	68
             - Commercial ornamentals	;	68
             - Avocados	69
             - Pecans	70
             - Livestock	71
       2. Above—shoulder spray applications: backpack or
          hand pressure equipment	72
             - Forestry	73
             - Homeowner ornamentals	73
             - Christmas trees (foliar application)	74
       3. Structural treatments 	75
       4. Dip applications	75
             - Hardwoods	76
             - Dog dips	77
             - Dog shampoos	78
       5. Enclosed area sprays	80
             - Moth sprays	80
             - Fumigation devices	«	81
             - Uninhabited building and storage bin sprays	82
       6. Dusts	82
             - Seed treatment.	82
             - Cog dusts	83
       7. Below-shoulder sprays	84
             - Cucurbits	84
             - Christmas trees (stump/slash)	84
   '  ,  8. Pre-plant soil application 	85
             - Pineapples	85
       9. Other household products (flea collars, shelf paper, and
               household sprays)	85
    E. Summary Conclusion on Dietary Risk	86
    F. Risk/Benefit Considerations Which Apply to All Lindane
               Products	87
       1. Accidental Misuse	87
       2. Aquatic Contamination Concerns	87
    G. Voluntary Actions To Which Registrants of Technical Lindane
               Have Agreed:  Mutagenicity Testing	87

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VIII. SUMMARY OF REGULATORY DETERMINATIONS	90

APPENDIX I:   Garments from the Secretary of Agriculture	96
APPENDIX II:  Garments fran the Scientific Advisory Panel	104
APPENDIX III: Exposure Analysis	108
APPENDIX IV:  Mutagenicity Testing of Lindane: Suiranary Table	131
APPENDIX V:   List of Abbreviations	135

COMMENT REFERENCES	,	136
REFERENCES	137
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I. INTRODUCnON

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The U.S. Environmental  Protection  Agency  (EPA or Agency) regulates all pesticide
products under authority  of  the Federal Insecticide, Fungicide, and Rodenticide
Act (FIFRA), as amended (  7  U.S.C.  136 et seq.).   Section  6(b) of FIFRA
authorizes the Administrator of EPA to issue  a  notice of intent either to
cancel the registration,  or  to change the classification of a pesticide product
if in his judgement either the pesticide  or its labeling does not comply with
the provisions of  FIFRA,  or  causes unreasonable adverse effects to human
health or the environment.

EPA designed the Rebuttable  Presumption Against Registration  (RPAR) process,
described in 40 CFR 162.11,  to gather and analyze  data on  the risks and
benefits of pesticides, and  to allow all  interested parties to participate
by submitting information relevant to the Agency's presumption.  The RPAR
process may be initiated  against any pesticide  which the Agency has
reason to believe  may cause  unreasonable  adverse effects.  This determination
is typically based upon a finding  that the pesticide meets or exceeds certain
"risk criteria", which  are defined in the regulation (ibid.).

In the FEDERAL REGISTER of February 17, 1977  (42 FR 9816), EPA published an
RPAR notice for pesticide products containing lindane.  It cited three risk
criteria which lindane  met or exceeded:   oncogenic effects (40 CFR 162.11
(a) (3)  (ii) (A)), reproductive and fetotoxic leffects (40 CFR 162.11 (a) (3)
(ii) (B)), and acute toxicity to aquatic  wildlife  (40 CFR  162.11 (a) (3) (i)
(B) (3)).  Additional concerns for which  the  Agency requested information
were: population reduction in avian wildlife, acute hazards to humans and
domestic animals,  hematoxic  effects (blood dyscrasias) in humans, mutagenicity
and isomerization  (several other isomers  of benzene hexachloride are known
to be oncogenic).

On July 21, 1978,  EPA announced in the FEDERAL  REGISTER that it had asked
registrants of benzene  hexachloride (BHC), which contains  lindane and other
isomers, to amend  their registrations.  Specifically, BHC registrants
voluntarily agreed to eliminate from their formulations the alpha and beta
isomers of BHC, which are established carcinogens, and to substitute lindane.
Lindane is by far  the most insecticidally active BHC isomer, and must be at
least 99% pure gamma isomer  for purposes  of registration with EPA.  The
substitution plan  eliminated the use of BHC products in the United States.
The amended lindane-containing products were  then  subject  to the lindane RPAR.
The regulatory decision described  in this document is therefore based on
test data for 99%  or greater gamma isomer of  BHC,  and should not be con-
strued to apply to BHC  or to products containing greater than one percent
of the other BHC isomers.

Following the 1977 RPAR announcement, EPA reviewed comments ("rebuttals")
from affected parties,  and analyzed the human and  environmental risks and
benefits of lindane's pesticidal uses.  A preliminary regulatory decision
("Preliminary Notice of Determination") was published in the FEDERAL REGISTER
of July 3, 1980 (42 FR  45362).  The basis and details of the preliminary
decision were described in Lindane Position Document 2/3 (PD 2/3) (EPA, 1980a).
The PD 2/3 described and  incorporated the comments received since the lindane
Position Document  1  (PD 1),  and presented the course of action the Agency
proposed to take,  based on an analysis of the risks and benefits of repre-
sentative uses of  lindane. *


*  The human pharmaceutical  use of lindane for  treatment of lice and
   scabies was not included  in the Agency's assessment since it has
   been under the  jurisdiction of  the U.S. Food and Drug Administration since
   1979  (44 FR 63749).
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The decision EPA proposed in 1980 was primarily based on a determination  that
the potential oncogenic and reproductive/fetotoxic effects of lindane
constituted risks to humans which were not sufficiently outweighed by the
benefits of lindane's use.

In addition, concern that lindane might cause acute effects to the central
nervous system (CNS), even though the risk criterion for acute toxicity was
not exceeded, led the Agency to conclude that as a CNS stimulant, lindane
posed significant risks to humans, and that children might be especially
sensitive to these effects.  The presumption that lindane causes acute hazards
to aquatic wildlife was withdrawn, since no lindane products were still
registered for direct aquatic application.  Existing data did not support a
presumption of mutagenicity, but several studies were interpreted as showing
positive mutagenic responses, and were considered to reinforce EPA's
presumption that lindane was an oncogen.  There was insufficient evidence to
establish a cause-effect relationship between lindane and blood dyscrasias,
but EPA expressed continued concern that the hematopoietic tissues of certain
individuals, particularly children, might be unusually sensitive to lindane.
There was also insufficient evidence to initiate a rebuttable presumption on
the basis of population reduction in nontarget avian species.  On the issue
of iscmerization, EPA concluded that microbial isomerization was not
significant, and that isonerization of lindane does not take place to any
appreciable extent in plants or animals.

As required by FIFRA, EPA considered the extent to which these risks were
offset by social, economic, or environmental benefits, and whether regulatory
action could decrease the risks without unduly .reducing the benefits.  The
details of this risk-benefit analysis are set forth in this Position Document 4.

Based on its analysis, EPA will initiate the following regulatory actions:

  1. Fumigation devices: cancellation of registrations for indoor use.
  2. Commercial ornamentals, avocados, pecans, livestock, Christmas trees,
     structural treatments, forestry, structural uses, dog dusts and dog
     wash uses: restricted use classification, label warnings to users,  and
     protective clothing for applicators;
  3. All other uses: modify labels as appropriate to reduce risks.

As is also required by FIFRA, SPA submitted the lindane analysis and proposed
regulatory decision to the Secretary of Agriculture, and the FIFRA Scientific
Advisory Panel (SAP), for comment by the former as to its impact on the
agricultural economy, and by the latter as to its impact on health and the
environment.  Concurrently, the Agency provided its decision document for
external review by other interested persons, who were notified of the
availability of the PD 2/3 by publication of a Notice of Availability in the
FEDERAL REGISTER (ibid).  All parties were allowed the same period of time
to comment (30 days) that the statute provides for receipt of comments from
the Secretary of Agriculture and the SAP.

EPA received comments from 141 parties, including the Secretary of Agriculture
and the SAP.  The latter two responses are reproduced in their entirety in
Appendices I and II.  Other comments are summarized and discussed in other parts

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of this document, according  to their  content.

This document  is organized as  follows: Chapter  I  is this Introduction,
Chapters II, III, IV and V contain  summaries of the comments and information
received on the health and environmental  concerns, exposure, and benefits of
lindane.  In each case, EPA  provides  its  analysis of these comments, and a
final conclusion.   In Chapter  VI, EPA summarizes  those considerations which
were most important in reaching its regulatory conclusions on lindane.
These key considerations are then used in the risk-benefit analyses in Chapter
VII, which describe the Agency's rationale for  the regulatory actions it
intends to take.  Lastly, Chapter VIII discusses several regulatory actions
which will be  taken on all the pesticidal uses of lindane, and presents an
overview of EPA's decisions  for the  various use groups.  Explanations of the
differences in the  PD 2/3 and  PD 4  exposure analyses are described in Appendix
III.

All nonconfidential comments received by  EPA regarding this document, are
available for  review in the  public  file located in the Document Control Office,
roan 236, 1921 Jefferson Davis Highway, Arlington, Virginia 22202.
     '           '                                                 '
A draft of the PD 4 (dated Feb.  23, 1983)  was sent to the California
Department of  Food  and Agriculture  (CDFA),  the Food and Drug Administration
(FDA), the Natural  Resources Defense  Council (NRDC), the National Audubon
Society, five  peer  reviewers of the former Scientific Advisory Panel,
and to the Centre International d'Etudes  du Lindane (CIEL) for comments.
The Agency has considered these comments  and has addressed all substantive
issues during  its reevaluation and  revisions of the PD 4.  The comments
are each addressed  within the  appropriate section of this document.
Four of the comments (FDA, CIEL, and  two  peer reviewers) essentially
supported the  EPA position document 4.  Suggestions to improve the con-
clusions and rationale were  considered and are  incorporated throughout
the PD-4 document.  Two commenters  (NRDC  and the National Audubon Society)
basically disagreed with the PD-4 draft,  and the Agency's departure from
the position taken  in the PD 2/3.   The Agency believes that this departure
is now sufficiently addressed  and is  based on a re-examination of the
benefits of lindane, a more  precise exposure determination, and a reevalu-
ation of toxicity studies.   Three peer reviewers while basically support-
ing the PD-4 position, disagreed with the retention of household uses of
lindane (i.e., the  unrestricted uses).  The Agency concludes that because
the risk estimates  for most  of these  uses are extremely low, cancellation
would be arbitrary  and not based on its own scientific conclusions.
However, the Agency will cancel the indoor use of the smoke fumigation
devices and dog dips for control of pests other than mites because the
cancer risk is unacceptable.   One commenter (California Department of
Food and Agriculture) suggested that  the  question of lindane1s oncogenic
potential be reevaluated by  a  group of experts.  The Agency believes
that further evaluation by another  panel,  using the same data base,
would not provide any additional information in support of the Agency's
regulatory position, nor would it settle  the ongoing scientific arguments
concerning the severity of lindane1s  (and other similar chemicals)  oncogenic
potential.  In fact, the Agency concludes that  it has used a very conservative
approach to estimate the cancer risk  of lindane although it is considered
a "weak" oncogen by many experts.

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II. HEALTH AND ENVIRONMENTAL CONCERNS

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A.  Trie  Presumption of  Cncogenicity

     1.  EPA's  PD  2/3 Position

In Position Document 1,  the  Agency announced  a  presumption
of oncogenicity based on three laboratory studies  in which
lindane  caused  tumors in mice  (Goto et  al.,  1972;  Hanada
et al.,  1973; and  Thorpe and Walker,  1973).   After comple-
tion of  a  fourth study  of carcinogenicity of  lindane in mice
by the National Cancer  Institute  (1977) and a study demon-
strating carcinogenicity of  2,4,6-trichlorophenol, a metabo-
lite of  lindane, the EPA Carcinogen Assessment  Group (CAG,
1979) provided  a comprehensive review of  the  oncogenic
effects  of lindane based on  these  and other animal studies,
for use  in Position Document 2/3.   At that time, the quanti-
tative risk assessment  for 21  uses of lindane was  based on
tne one-hit model.  Using this linear low dose  model, the
slope factor for lindane was estimated  as 0.00732  (ppm)~l.

      2.  Comments on EPA's  PD 2/3 Position,  and PD 4 Final
Position

The Centre International d'Etudes  du Lindane  (CIEL), whose mem-
bership  is comprised of many of the manufacturers  of technical
grade lindane,  submitted extensive comments to  EPA on the
PD 2/3.  Many of the points  raised in CIEL's  comments were
addressed  in the PD 2/3.  The  following issues  were either
not raised before, or EPA has  since changed its position,
therefore  they  are discussed here  (Memo,  1982a).

          a.  Choice of an appropriate  risk assessment model

            i.  Comments on  EPA's  PD 2/3  Position

During the Scientific Advisory Panel  (SAP) hearings which
followed publication of the  PD 2/3 (July  24 and August 13-14,
1980), and also in the  submission  from  CIEL,  questions were
raised about the choice of an  appropriate model for extrapolating
risk from animals  to humans.   The  SAP suggested that it would be
more appropriate to use several models, to show the possible
range of risk,  rather than using only the one-hit  model.  CIEL
(Vol.- 1, page 38 and Exhibit 7, page  4) stated  that the one-hit
model "vastly over-estimates the true risk",  and proposed
using the so-called Weibull  model  instead.  Yet another model,
the Mantel-Bryan,  was proposed by  a third scientist within
EPA.  A  fourth  model, the multi-stage,  is also  a linear model
and is generally used by EPA in the absence of  another which
fits the data better.   '(Memo,  1982a).

The Paper Products submission  (30000/lOc  #93) raised the
possibility of  evaluating carcinogens differently  if the
mechanism can be shown  to be epigenetic rather  than genotoxic.
It was argued that lindane is  an epigenetic substance for
which it should be possible  to establish  safe threshold levels.

NRDC (1983) supports the Agency's  choice  of the linear risk
assessment model.

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            ii.  EPA's PD 4 Position

EPA agrees with the SAP that it is generally preferable to use more than one
model to estimate risk, especially when there is substantial uncertainty
regarding the choice of an appropriate model.  However, as detailed in the
CA3 memo (1982a), the lindane data are insufficient to make use of the alter-
nate models which have been suggested in this case.  In short, the statistical
basis necessary to draw up a range of risk estimates for lindane does not
exist (Memo, 1982a).

Other considerations also limit the scientific justification for using any
model other than the linear low dose model.  The following discussion of
cancer risk models is extracted from memo (1982a).

The mammalian mutagenicity data are insufficient to resolve whether or not
lindane is genotoxic.  In fact, it may be that lindane acts both as an
"initiator" (by a genotoxic mechanism) and a "promoter" (by as yet unknown
mechanisms).

The linear non-threshold dose-response relationship is consistent with the
relatively few epidemiological studies of cancer responses to specific agents
thafcontain enough information to make the evaluation possible (e.g., radia-
tion induced leukemia, breast and thyroid cancer, skin cancer induced by
arsenic in drinking water, liver cancer induced by aflatoxin in the diet).

In the most complete test yet made of animal carcinogenic dose response •
relationships [the large scale EDQ} study of 2-acetylaminofluorene in
mice at the National Center for Toxicological Research (NCTR)], the liver
tumor response was linear down to the lowest dose tested.  However, since
the bladder cancer response was non-linear in the same experiments, the
study implies that non-linear mechanisms also exist.
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Because it had the best, albeit limited, scientific basis of any of the
current mathematical extrapolation models, the linear (one-hit) non-threshold
model was adopted as the primary basis for risk extrapolation to low levels
of the dose-response relationship.  Risk estimates using the linear model
are regarded as plausible upper-limits, since it is possible that a non-linear
mechanism could be occurring, which would make the risk approach zero at
sufficiently low doses.  Based on the one-hit model and the other procedures
for estimating risk at the time of PD 2/3 in 1979, the potency, or slope
factor, for lindane was estimated to be b=0.00732(ppm)~^.

1)  Multistage Model

In early 1980, the CPG, following suggestions from outside statisticians and
other scientists, modified its procedure for estimating risks.  This procedure
is documented in the "Notice of Availability of Water Quality Criteria Documents"
(Federal Register, Vol. 45, No. 231, Friday, November 28, 1980, Notices p. 1).
Rather than extrapolate frcm the lowest dose, which shewed a greater response,
as had been the procedure using the one-hit model, the multistage procedure
used all data points that fit the model.  The extrapolation was based on
the largest linear component, which then fit the data.  Thus, the multistage
model is still linear at low doses.  The plausible upper-limit slope factor
for lindane based on the multistage model is b = 0.030 (ppm)~l.

2)  Mantel-Bryan Procedure

EPA has used the Mantel Bryan procedure to estimate lindane risks.  This
procedure was to start from the only treated dosage group of the Tunstall
study (incidence of 27/28 at 400 ppm in diet), calculate the 99% upper 'confi_
dence limit of this response (which was found to be 99.99% of the animals
responding), then use a log-probit slope of 1.0 to extrapolate to low
doses.  For a 10,000-fold reduction in dose, the risk is estimated to be
16%, whereas the linear multistage model gives 0.12% as the risk.  The
marked increase of estimated' risk (cotpared to a linear model) results frcm
the extremely nonlinear behavior of the log-probit function at the extreme
high end (close to 100% response) of the curve.  The practice of taking the
upper confidence limit of the high response puts one even further into the
non-linear region.  If the lindane response had been near 10% rather than
95%, the risk after extrapolating downward by a factor of 10,000 would have
been much less than that using the linear model,  Thus, results are unreliable
if the Mantel-Bryan procedure is used with data such as lindane.

The CAG does not consider this model appropriate for risk estimation for two
reasons: 1) the results are highly dependent on where the response data
happen to fall in the animal experiment, as explained above; and 2) the
results are highly dependent upon the arbitrary slope, which is chosen
independently of the data.  Mantel and Bryan chose a slope of 1.0 to be
"conservative", i.e., to intentionally overestimate risks, so that a small
acceptable dose would be chosen, which would be certain to protect public health.

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for quantitative risk extrapolation one should use the actual slope
determined from the data, which typically ranges anywhere from 1.5 to 5,
if one believes that the log-probit model really describes the cancer
dose-response relationship.  Mantel and Bryan did not intend to use this
log-probit model to estimate quantitative risks, merely a "virtually
safe dose," below which safety could be assured.  The Agency feels that
in this case, this approach is unnecessarily conservative.

3)  Weibull Model

Dr. Frank Carlborg of CIEL uses a generalization of the linear dose-
response model in which the dose, x, appears as the k^ power.   His
model, which he calls the Weibull model, i-s P (x) = 1 - exp - (a+bxk) .
But since lindane was tested at only one dose level in the Tunstall
experiment, not enough information is available from that study to estimate
a value for k.  Therefore, Dr.  Carlborg attempts to estimate the k
value for lindane by assuming that the k value for lindane is in the
same range as that for other hydrocarbons producing liver responses in
mice.  The k values for nine compounds were found to range between 0.33
and 4.5.  Since the largest experiment yet done, (the EDgi study by
NCTR), gave a k value of 1.49 and since that value is within the range
of variation of the chlorinated compounds, Dr. Carlborg assumes this
value of k for lindane.  To get a value for the slope parameter, b, he
used the one-hit slope derived from the Tunstall experiments.

In the opinion of the CAG, he is not justified in first assuming that, k
= 1.49 to get a value for a one-hit slope, b, and then choosing a different
value of k based on other experiments, and incorporating these  values
into the same model.  In the Weibull model these two parameters cannot
be independently estimated with any degree of certainty.  An examination
of Dr. Carlborg1s calculation shows such a wide variation in the estimates
of both b and k,  that virtually any risk estimates would be possible
when the Weibull model is used with the lindane data.

4)  Appropriateness of Various Models for Lindane Risk Assessment

The dose-response data for lindane are very sparse.   Only two positive
studies have been reported where there is an adequate number of animals
for conducting a risk assessment.  In one study (Thorpe and Walker, 1973)

-------
only one  treated dose  group was  tested, and  in  the other  [National Cancer
Institute  (NCI)] ,  two  doses were used  but  the highest dose produced a non-
significant  increase.  Thus, there are  only two  dose-response data points
which allow  for  the estimate of  only one parameter. The linear model, which
currently  takes  the form of the  linearized multistage model, gives a plausible
upper-limit  of risk, because most dose-response data appear to be either
linear or  to have  upward curvature,  at least in the low dose region.  Further-
more, the  linearized multistage  model  is felt to give a more reliable upper-
limit risk estimate when the carcinogen is also genotoxic.  The Mantel-Bryan
procedure !in the case  of the lindane data  is unreliable because the upper
confidence limit is so close to  an  incidence of 1.0 as to make any risk
extrapolations unreliable and  because  the  arbitrary slope of 1.0 probit
per log dose must  be used in the absence of  dose-response data.  The CIEL
"Weibull" approach is  simply a selection of  the dose slope parameter, k,
based  on other compounds.   Since any  value  k would fit the lindane data,
and a large  range  of k's fit data on similar compounds, no confidence can be
placed on  the accuracy of an extrapolation to low doses.

The most commonly  accepted  mechanism of carcinogenesis is the somatic cell
mutation theory, in which the  agent  causes an alteration in the genetic material
of a cell, which is replicated in subsequent generations.  This genetic change
can arise  from a single  molecular change in  the DNA of a cell with a proba-
bility that  is proportional to the applied dose.

In conclusion, there is  not enough  information  at this time to justify using
any risk model other than one  that  is  linear at low doses.  This is the
model commonly accepted  as  valid for providing  plausible upper-bound risk
estimates.   It is  also consistent with the commonly accepted mechanism of
carcinogenesis: the somatic cell mutation  theory.

As discussed in Chapter  VII, EPA has taken the  uncertainties described above
into account in its regulatory decision on lindane.  The Agency's decision
is specifically designed to reduce the uncertainty within a reasonable time
frame, while taking immediate  but minimally  burdensome steps to protect the
populations which  may  be at risk.  These regulatory measures may be revised
in the future, if  so warranted by significantly improved understanding of
lindane's carcinogenic mechanism in  animals, or other information relating
to its potential to cause cancer in  humans.  The CIEL and EPA have agreed to
the conditions under which  additional  information (testing) will be obtained.
Further details of this  agreement may  be found  in Chapter VII. , F.

         b.  Use of pooled  controls

             i. Corrtnents on EPA's PD 2/3 Position

Dr. Vesselinovitch (CIEL Volume  II,  p.26)  criticized the selection criterion
for the pooled controls  in  the NCI Mouse Study. He stated that the selection
criterion  "is not  scientific and tends to  bias  the controls in favor of a low
background tumor incidence".

             ii. EPA's PD 4  Position
                                    10

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Although the concern that the controls were not randomly chosen is a reasonable
one, a review of the data on the pooled controls shows 1) no significant
difference in hepatocellular carcinoma between the pooled controls and the
matched controls, 2) comparable survival between all five groups that made up
the pooled controls, and 3) comparable living and handling conditions, and
comparable weight gains, among all of the controls.  Furthermore, comparison of
the low-dose lindane results with yet a larger, and different, pooled control
group which MCI used for another chemical (endrin) also shows a significant
response at the p = 0.05 level.  Based on these considerations, EPA believes
that the use of the pooled controls for analysis of the lindane data is both
proper and justified (Memo, 1982a).

         c.  Tumor classification
            i. Comments on EPA's FP 2/3 Position

In his evaluation of the Tunstall lindane data (Thorpe and Walker, 1973), Dr.
Vesselinovitch scores fewer tumors as hepatocellular carcinoma than do Thorpe
and Walker.  The tumors that Dr. Vesselinovitch does not call hepatocellular
carcinomas are classified by him as either adenomatous nodules or. adencmatoid
(hyperplastic) nodules.  He further argues that benign and malignant lesions
should not be analyzed together, since he claims that they are different
biological entities. (CIEL, Vol. II, pp. 37-38).

            ii. EPA's PD 4 Position
EPA acknowledges that there are differences of opinion among patholegists as
to the proper classification scheme for mouse liver tumors, particularly the
benign nodular lesions.   There are also differences regarding the categorization
of specific mouse liver lesions.  However, even with Dr. Vesselinovitch1s
evaluation scheme, there is a statistically significant incidence of
combined hepatocellular carcinomas and adenomas, which is evidence for a
tumorigenic response to lindane in mice.  Furthermore, until there is
evidence to the contrary, EPA assumes that hepatocellular adenomas and
carcinomas are biologically related,  and may represent different stages of a
continuous biological process.  Thus, it is appropriate to combine these
incidences for risk assessment purposes (Memo, 1982a).  NRDC (1983)  endorses the
Agency's position regarding tumor classification.

         d.  IARC classification of lindane

             i. Comments on EPA's PD 2/3 Position
                                                   \
Dr. Vesselinovitch (CIEL Vol. II, pages 73, 87, and Appendix F)  states that
the International Agency for Research on Cancer (IARC) classifies the avail-
able scientific data for lindane carcinogenicity as limited for animals and
inadequate for humans, whereas he concluded that lindane _is not carcinogenic
in mice.
             ii. EPA's PD 4 Position

Actually, IARC states that there is sufficient evidence for the carcinogenicity
of lindane (gamma-HCH) in mice (IARC Vol. 20, page 223), limited evidence in
animals, and inadequate evidence in man (Memo, 1982a).
                                    1  1

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         e.  Alpha-fetoprotein levels  in  the  Hanada  study

             i. Comments  on  EPA's PD 2/3  Position

In discussing  the Hanada  et  al.  study  (1973)  on  lindane, Dr. Vesselinoviten
(CIEL Volume II, page  42)  states that  the alpha-fetoprotein levels are only
elevated in animals  bearing  true neoplastic lesions.  Since these sera levels
were not elevated in the  mice  that had nodular lesions  (according to Hanada
et al.), Dr. Vesselinoviten  states that "none of the  nodular lesions was
true neoplasia", based upon  the' negative  alpha-fetoprotein sera levels.

             ii.  EPA's PD 4 Position

The Hanada et  al. (1973)  study measured alpha-fetoprotein levels by the
Ouchterlony method using  antiserum obtained from the  horse immunized with
human alpha-fetoprotein.   Becker and Sell (Cancer  Research 34: 2489-2494,
1974) and Becker et  al. (Cancer Research  35:  1510-1513, 1975) have actually
shown that alpha-fetoprotein levels (measured by the  rat alpha-fetoprotein
radioimmunoassay technique)  are immediately increased in rats after car-
cinogen exposure and before  any pathologic alteration can be detected.  In
mice, Becker et al.  (Cancer  Research 37:  870-872,  1977) and Becker and Sell
(Cancer Research 39:3491-3494,1979) reported  elevation of serum alpha-
fetoprotein levels observed  in a majority of  animals  with liver tumors,
using their mouse alpha-fetoprotein radioimmunoassay  technique.  Dr. S. Sell
(telephone conversation with Dr.  Haberman, CAG,  Dec.  15, 1981) stated that
the Ouchterlony method used  in the Hanada et  al. study was not very sensitive
or reliable, when compared to  the mouse alpha-fetoprotein radicirnmunoassy
using radiolabeled mouse  alpha-fetoprotein.   Therefore, even though the Hanada
et al. study reported  that the mice with  liver tumors had negative alpha-
fetoprotein levels,  the Agency believes that  the reported tumor results of
this study show a carcinogenic response to lindane administration in these
mice.

         f.  Tumor classification in the  Goto et al.  (1973) study
             i. Comments  on  EPA's PD 2/3  Position

Dr. Vesselinovitch (CIEL  Vol.  II,-pages 37-38) stated that the tumors observed
in the Goto et al. study  are hyperplastic nodules  consisting of normal-appearing
cells, rather  than hepatocellular tumors.

             ii. EPA's PD 4  Position

The English translation of the German  article states  that "Hepatoma I - The
tumor is a limited,  small  hyperplastic growth, grey-white, which has the
appearance of  a benign neoplasm (gutartiges Neoplasma) in the early stage....
The accumulated encapsulated ceils press  against the  surrounding tissue, but
they normally  do not grow into the tissue".   These authors continue to say that
"Under the same experimental conditions,  beta- and gamma-HCH also cause
Hepatoma O-I (a benign liver tumor)."   Therefore,  Goto et al. (1973) are
referring to a benign  neoplasm causing local  compression, i.e., by definition
a hepatocellular adenoma,  not  a hyperplastic  nodule,  as Dr. Vesselinovitch
states (Memo,  1982a).

         g.  Possible  cross-contamination -in  the NCI  bioassay



                                        12

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             i. Cerements on EPA's PD 2/3 Position

The submission from Paper Products (rebuttal #93) raises the possibility of
cross-contamination by other carcinogens to the lindane-treated animals in the
NCI bioassay, as an explanation of the high tumor incidence of the low-dose mice.

             ii. EPA's PD 4 Position

Although cross-contamination of the external environment in which these studies
took place has been documented, there is no evidence suggesting contamination
of the feed or cages (which were in any case protected by filter bonnets.)
Furthermore, if cross-contamination had occurred, one would expect to see an
increase in tumor incidence in the matched-control group, not just the low-dose
test group.  However, the carcinogenic response in the matched-control group is
net significantly different from the historical-control group.  Therefore, EPA
does not consider that cross-contamination explains the differences in tumor
response between treated and control groups (Memo, 1982a).

         h.  EPA's PD 4 Final Position on the Presumption of Oncogenicity

The evidence that lindane is carcinogenic in mice is based on two lifetime
studies, Thorpe and Walker, and the NCI study both of which show that oral
administration of lindane causes hepatic tumors.  Two subchronic studies in
mice (Goto et al., Hanada et al.,)  provide supportive evidence of oncogenicity
consistent with that found in the two lifetime studies.  Consistent with more
recent risk assessment approaches,  the CAG has used the multi-stage model for
a revised slope of 0.03 (ppm)~l for the cancer risk estimates for PD 4.  In
addition to chronic bioassays of lindane itself, 2,4,6 trichlorophenol, a
metabolite of lindane in rats and humans, was tested and found to be a
carcinogen in laboratory animals.  These tests will be discussed below.  In
addition, the following sections will address in vitro as well as in vivo
metabolism, mutagenicity testing of lindane and the cancer bioassays.  The
genotoxicity issue for lindane and its importance for quantitative risk
assessment will be considered in light of these related effects.

The NRDC (1983) is disturbed by reports "that the Agency views only two of the
four studies as evidence of 'lindane's carcinogenicity."  The preceding paragraph
clearly indicates that the Agency believes lindane causes carcinogenic responses
in mice.  That position has not changed from PD 2/3.  As stated, the position is
based on two lifetime feeding studies with supportive evidence from two sub-
chronic studies.  None of the four studies has been "discounted" and all four
are considered positive evidence of oncogenicity in mice.  Moreover, a very
conservative risk extrapolation model has been used to estimate the cancer risks.

         3.  Metabolism of Lindane
\
Extensive metabolism of lindane occurs mainly in the liver through
dehydrogenation, dehydrochlorination, hydroxylation and oxidation.  Many
of the resulting metabolites appear as water soluble conjugates in the
urine.  Fitzloff, Portig and Stein  (1982) studied metabolism of lindane by
human and rat liver microsomes under aerobic conditions while Chadwick et
al., (1981) have tabulated urinary  metabolites of lindane from studies in
rodents.  Chadwick (1978)  also studied the in vitro metabolism of lindane
under anaerobic conditions.  Metabolites include hexachlorocylohexene,
pentachlorocyclohexene, tetrachlorophenol, trichlorophenol, pentachloro-
cyclohexenol and tetrachlorocyclohexenol.


                                    13

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However, as shown  by  these and other researchers,  the total quantitative
and qualitative profile  of lindane metabolites  is  a function of species
and experimental conditions (see also C£G,  1979).  Therefore, any
toxicity testing of lindane must take these variations into account.
For example under  anaerobic conditions,  incubation of lindane with rat
liver microsomes leads to two novel  metabolites not found under aerobic
conditions.

Certain metabolites of lindane are consistently identified no matter what
the conditions or  test species.   One of  particular interest is 2,4,6-
trichlorophenol.

This metabolite, which is also observed  in  human urine (Starr and Clifford,
1972), has been found to be carcinogenic (see below).

In addition to membrane  bound enzyme systems (microsomes), lindane
may also be metabolized  by cytosolic enzymes.  In  an _in vitro study,
Portig et al. (1979), concentrated on glutathione  conjugate formation
of lindane incubated  in  vitro.   They found  that conjugate formation of
lindane occurred only in the presence of liver cytosol protein as a
source of glutathione transferases,  implying that  conjugation is enzymatic
in nature.  Van Bladeren et al.  (1981) has  shown that other vicinal dihalogen
compounds can be activated to mutagenic  2-halogenothioethers by conjuga-
tion with glutathione.   Steric factors in the substrate can be important
in determining whether the halogenothioether can be formed and whether
it will be mutagenic.  To date the role  of  glutathione and thioether
formation in the mutagenicity of lindane has not been tested.

         4.  Mutagenicity

In the initial lindane RPAR,  the Agency  did not determine that the mutagenicity
criterion has been exceeded.   However, a review of mutagenicity studies on
lindane is discussed here because of their  bearing on the carcinogenicity
issue.  Lindane mutagenicity testing is  summarized in Appendix IV.

Lindane has been tested  for:

0 gene mutations in microbial systems (Ames, yeasts, and Drosophila);
0 chromosome aberrations in mammalian systems (in  vitro and
  in vivo);
0 other cellular end-points related  to genotoxicity (DNA repair, and
  mitotic abnormalities  in plant and mammalian cells); and
0 mammalian cell transformation
0 binding to DNA (C.I.E.L.  sponsored, recently completed).

The composite of these studies reveals limited evidence for lindane1 s
mutagenicity or genotoxicity (see Appendix  IV).  Except for two
Salmonella studies by Rohrborn,  gene mutation assays were negative in
bacteria, yeasts,  and Drosophila.  Although there  is a "suggestion" in
some older studies for chromosomal effects  (e.g.,  Tzoneva-Maneva, 1971, who
reported slight increases in chromatid breakage and gaps), the majority of
cytogenetic studies were reported as negative.  Studies supposed to test for
the integrity of cellular repair processes  in bacterial and mammalian
cells were also negative,  as were cell transformation assays with human

                                     14

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and namster cell lines.  Lindane has also been shown to have little or no
genetic activity employing more sensitive tests for detecting DNA events.
For example, negative results were reported in bacterial Ames testing
in the presence of a microsomal metabolic activation system  (S-9) from
tne tumor-susceptible mouse strain, CF-1.  Negative results were also
obtained in the presence of inactivators of potential nucleophilic reacting
products, such as the epoxide hydrase inhibitor and glutathione depletor,
1,1,1-trichloropropene (TCPO), as well as following preincubation with
nor-harman, a DNA intercalator and co-carcinogen, which is a known inhibitor
of DNA synthesis and repair.

Some.studies have reported spindle inhibition with lindane, but these have
not been validated by EPA.  That lindane may act as a spindle inhibitor is
suggested by its cytological activity in plant cells, in which it produces
c-mitosis and polyploidy, and in rat liver cells, where it increases mitotic
indices and tetraploidy.  However, other (non-validated) studies reported
negative results (e.g., deBrabander 1976).

In the array of conventional mutagenicity assays already performed with
lindane, however, a number appear to be missing (see Appendix IV).
Chlorinated hydrocarbons present particular difficulties in short-term
testing.  Therefore, in addition to conventional testing with standardized
hepatic microsomal fractions, adjustments in activation conditions would
appear to be necessary for lindane.

In order to be considered valid, _in vitro assays with lindane, would have
to be performed under conditions as closely representative as possible of
liver metabolism in_ vivo, e.g. presence/absence of oxygenation, time course
of treatment, processing, etc.  This is necessary because of metabolic
considerations indicated in published studies with such organochlorines.
For example, Sipes et ai. (1977) conducted in vitro studies which indicate
that the bioactivation of chloroform to species capable of binding to
proteins, involves a cytochrome P450-dependent oxidation, and not a reduction,
as found for carbon tetrachloride.  Two separate groups, Mansuy et al.
(1977) and Pohl et al.  (1977) reported evidence that biotransformation of
choroform to phosgene can occur.  Both groups were able to trap, isolate,
and identify a cysteine conjugate of phosgene that was produced when
chloroform was incubated with microsomes in vitro.  Cn the other hand, _in
vivo metabolic studies by Brown et al.  (1974) have shown that   CHCl-j
is rather extensively converted to ^O^.  With the exception of recent
work by Oesch (1980), none of the investigations listed in Appendix IV
have addressed the necessary activation conditions as described above.
Even the Oesch work failed to utilize the cytosolic fractions of liver
preparations known to contain essential enzymes for the metabolic processing
of ocenobiotics, such as the sulfotransferases and dehydrogenases required
to convert intermediates ("proximate" carcinogens) into their most highly
reactive ("ultimate" carcinogens) forms which are not found in the customary
microsomal fractions employed in testing.

NRDC (1983) questions why the Agency did not "validate" the studies that report
spindle inhibition and why the Agency is "dismissing lindane's potential
mutagenicity" in light of a number "conventional mutagenicity assays that appear
to be missing."  First, there are currently NO validated testing procedures
specifically designed to assay directly for spindle inhibition (Mauer, 1983).
                                     15

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Tnus, there  is  no standard  method available by which to  judge  sucn  studies.
Second, the  Office of- Pesticides Programs  has  an agreement with CIEL  to
fulfill rrutagenicity  testing requirements  under provisions of  FIFRA,  40 CFR
153  (found in 47 FR 53192-53221 "and  48  FR  2142-2147).  The agreement  was
concluded on March 25,  1983.  Mutagenicity was not one of the  RPAR  triggers.
In spite of  that, the Agency has not "dismissed" the subject of potential
mutagenicity.   It is  seeking to extend  its knowledge beyond the conventional
battery of assays presently required for pesticide registration or  reregis-
tration (Mauer, 1983).   Since there  is  currently limited evidence that! would
indicate the Agency should  be concerned about  mutagenicity, the data  gaps
need not be  filled prior to completion  of  the  RPAR.   The information  in
the studies  will aid  in the understanding  of mechanisms  of oncogenesis.

Therefore, because of the data gaps  in  required testing, and insufficient
consideration of exogenous  activation in the tests performed,  a conclusive
evaluation of lindane's genotoxicity is not. possible at  this time.  However,
further testing will  be done by the  Centre International d1 Etudes du  Lindane,
as explained in Chapter VII., F.

5.  Bioassays of Lindane and its Metabolites in Laboratory
    Animals.

Although lindane has  been tested extensively for carcinogenic!ty in
laboratory animals, there are very few  lifetime studies.  Cnly two  life-
time studies have been performed at  the Maximum Tolerated Dose (MTD)  in mice,
Other mouse  studies were of limited  duration or dosages were low.   Several rat
studies have been performed, but with the  exception of the NCI study  in rats, these
rat studies  are severely limited on  their  utility as cancer bioassays
by the small numbers  of animals or short duration of testing.  The  nost
important mouse and rat studies are  summarized below.- For details  on
the data base examined by the Agency, the  reader is referred to the CAG
Risk Assessment on Lindane  (1979).

Thorpe and Walker (1973) reported on the Tunstall Laboratory mouse  study.
In this lifetime study, 30  CF]_ mice  of  each sex were treated with a
single oral  dose, 400 ppm,  of lindane (See Table 1 for details).  A signifi-
cant increase of liver tumors was found in the treated animals relative
to the controls (96%  in treated males and  95%  of the females compared to
24% and 23%, respectively,  in the controls).   In addition, there was
evidence of  tumor metastases to the  lungs  in both sexes.

In 1977, the NCI published  the results  of  a lifetime bioassay  of lindane
in B§C3F]_ mice.  Test groups of 50 male and 50 female mice were fed
lindane at 80 or 160  ppm.   The incidence of hepatocellular carcinomas in
low dose males  (19/49)  was  significant  when compared to pooled controls
(5/49), but  not in high cose animals.

Hanada et al. (1973)  fed dd strain mice 100, 300 or 600 ppm lindane for
32 weeks.  Sacrifice  occurred at 37  or  38  weeks.   Mortality in the  treated
groups was very high.   However, malignant  hepatomas  were found in 3 out
of 4 surviving males  and 1  out of 3  surviving  females in the high dose
group compared with 0 out of 14 in the  male controls and 0 out of 15
                                      16

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mortality and the short duration of the study, the high incidence of
tumors noted above in 38 weeks of testing indicate that lindane may be
carcinogenic in this strain of mice.  This study, although flawed, sup-
ports the results of the other studies because it indicates that even a
relatively short exposure to lindane may also induce tumors in mice.

In a 26-week study, Goto et al., (1972) fed ICR-JCL mice 300 and 600 ppm
lindane.  Five of ten surviving mice in the high dose group had liver
tumors.  Some of these tumors were classified as benign.  Control group
pathology was omitted.  The CA3 report notes that in Goto et al., as
well as Hanada et al., liver lesions consisted of foci of altered cells
with atypical appearance, consistent with the early stages of hepatocel-
lular carcinoma.  Although 50% of the high dose group developed tumors
after a short period, it is difficult to definitively interpret the
results because pathology in the controls was not reported.  However,
because of the young age of the animals and the short duration of the
experiment, this study is consistent with the positive results seen in
the other studies.

In the four studies described above, data are consistent in that males
were more susceptible than females and the liver was the primary site of
tumor development.  In other mouse feeding studies, Ito et al., (1973) and
Nagasaki (1972) gave lindane to male dd mice for 24 weeks.  At high doses',
there was liver hyperplasia, but in this short study, neither carcinomas
nor hyperplastic nodules were found.  Herbst et al. (1975) also performed
two lifetime feeding studies in mice at low dose levels.  No tumors were
found.

In 1977, the National Cancer Institute published a bioassay for lindane in
Osbome-Mendel rats.  Fifty rats of each sex were fed lindane at 135 to
472 ppm for 80 weeks and subsequently observed for 29—30 weeks.  The
report concluded that no tumors occurred at a statistically significant
incidence in the treated group of either sex.

As noted earlier, the remaining data base in rats is of limited utility
because of short duration of testing or small numbers of animals tested.
Sunmaries follow.  Ito et al., (1975) fed male Wistar rats 500 pan of
lindane for 24 or 43 weeks.  Survival was poor.   Six treated rats were
sacrificed at 24 weeks and 8 at 48 weeks.  Slight hyperplasia was found at
48 weeks, but no neoplasia.  Fitzhugh at al. (1950) fed groups of 10 female
and 10 male Wistar rats 5 to 1600 ppn lindane for up to 107 weeks.  Survival
was poor.  In 5-16 animals per dose group, toxic effects were observed in
the liver down to 100 ppm, but no carcinogenic!ty was observed.  Ortega et
al'., (1957) fed Sherman rats 50 and 100 ppm of lindane for up to 8 months.
Serial sacrifices of one rat per sex per dosage group were performed at
2, 4 and 6 months.  Three rats per sex per dose were sacrificed at 8 months.
Liver toxicity was observed, but no evidence of carcinogenicity was found
under the conditions of the study.  Truhaut (1954) fed 10 male and 10
female rats per dose group, 25, 50 and 100 ppni lindane for their lifetimes.
No cncogenicity was observed; however, slight liver hypertrophy was observed
at 50 ppm and 100 ppm.  No toxic effects were seen at 25 ppm.

In 1979, the NCI released a report on a bioassay of the lindane metabolite,
2,4,6-trichlorcphenol in F344 rats and BgC3Fi mice.  The animals were


                                    17

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fed the test chemical at 5,000 and 10,000 pptn.  Halfway through the study,
dosage for the mice was halved due to high mortality.  Male rats showed a
significant increase in leukemias or lymphcmas.  Females shewed increased
significance of hyperplasia of peripheral blood elements and bone marrow at
both doses.  Both male and female mice exhibited dose related increases in
heoatocellular carcinomas or adenomas.
                                    18

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                                             Table 1
                            Caroariscns of Mouse Bicassavs of Lindane
--Protocol
 - Strain

  Ace

  Sex

  Number/group

  Dcse (pan)
  in diet


  Duration


  Results
      NCI
      studv,
      1977"
    Thorpe &
    Walker,
    1973
  Goto
  et al.,
   1972
35 days

both

50

80
160
80 weeks and 10-11
weeks of observation

Hepatocellular car-
cinoma in male mice
at low-dose level
of 80 pan (19/49;
P=0.001) High dose
group not signifi-
cant" (9/46 vs. 5/49
P=0.16).
4 weeks

both

30

400



 110 weeks
Liver tumors in
males and females.
96% males and 95%
females treated
vs. 23-24% of
controls (P less
than 0.0001),
5-11% lung metas-
tases.
IRC-JCL

5 weeks

male

20

600
300


26 weeks
Liver tumors
in males (50%
of treated
males at 600
ppm; P=O.Q16)
No tumors re-
   Hanada
   et al.,
    1973
dd

6 weeks

both

10-11

100
300  .
600

37-38 weeks
Liver tumors
in males and
females (3 of
4 surviving
males; 1 of 3
feniales at 600
                                                            ported in con-  pom;  No tumors
                                                            trols.          in  controls.
                                                                           Significant in
                                                                           males (?=0.005
                                                                           at  600 ppm).
                                              19

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      6.  Quantitative Risk Assessment of Lindane

In the  Lindane  Position Document  2/3, the Carcinogen Assessment Group estimated
the carcinogenic potency of lindane as b = 0.00732  (ppm)~l using the one-hit
model.  At low  doses  this model is a linear, non-threshold dose-response
model.  The Agency has considered the use of non-linear models for carcinogenic
risk assessment of lindane.  However, as noted above, only two positive
studies have been reported in  which the number of animals was sufficient for
purposes of risk assessment.   In  one study (Thorpe  and Walker) , only one
dose group was  tested, and in  the other (NCI), only one dose group showed a
significant response.  Under these circumstances, the data base is not sig-
nificant for the use  of any model but a linear one.  In its rebuttal analysis,
CAG describes in detail the reasons for using a linear model and its choice
of the  linearized multi-stage  model for the Position Document 4 consistent
with current risk assessment approaches.

The linear model gives plausible  upper limits of risk.  Using the linearized
multi-stage model with a 95% upper confidence limit estimate and the further
assumption that doses in mice  and humans were equivalent on the basis of
surface area (calculated as mg/kg b.w.) CAG estimates the linear slope factor
as q* = 0.03 (ppm)~l.  The new slope estimate is 4.1 times larger than
the old slope estimate because of two contributing  factors as follows:

     (a)  2.83  due to a different method of estimating human
          equivalent  dose (surface area rather than dietary ppm) .

     (b)  the remaining factor of 1.45 due to the use of an upper confidence
          limit approach in the current multistage  exprapolation procedure,
          rather than a point  estimate for slope used earlier.

7.  Summary

The evidence that lindane is carcinogenic in mice is based on two lifetime
studies, Thorpe and Walker, and the NCI study both  of which show that oral
administration  of lindane causes  hepatic tumors.  Two subchronic studies in
mice (Goto et al., Hanada et al.) provide supportive evidence of oncogenicity
consistent with that  found in  the two lifetime studies.  In three of these
four studies, liver tumors were consistently found  in males.  In one, Thorpe
and Walker, male and  female mice  exhibited liver tumors.  Lung metastases were
observed as v/ell in the Thorpe and Walker Study.  No evidence for oncogenicity
of lindane has  been found in rats.  With the exception of the NCI lifetime
bioassay, the other rat studies had severe limitations with respect to test
duration and numbers  of animals studied.  However,  2,4,6-trichlorophenol, an
animal and human metabolite of lindane, has been shown to cause lymphomas or
leukemias in rats and hepatocellular carcinomas in  male and female mice.  To
date, mutagenicity testing has been inconclusive and therefore the genotoxicity
potential of lindane  is indeterminate.

In conclusion,  there  is strong positive evidence that lindane causes hepatic
tumors  in mice.  In addition,  2,4,6-trichlorophenol, a metabolite of lindane,
                                     20

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has been found to be carcinogenic in both rats and mice.  Until further,
mutagenicity testing is performed, the genotoxicity of lindane can neither be
confirmed or refuted.  Because the biological data base for lindane is inade-
quate for a definitive choice of models, the linearized multistage model was
used for PD 4 to provide a plausible upper limit risk estimate by extrapolating
the risk linearly to low doses.  In light of the carcinogenic effects of lindane
in mice and the evidence of carcinogenicity of a metabolite of lindane in rats
and mice, the Agency belives that lindane should be considered to have the
potential for inducing carcinogenic effects in humans at some exposure level.

B.  The Presumption of Fetotoxicity/Reproductive Effects

      1.  EPA's FD 2/3 Position

EPA's presumption that lindane might cause reproductive and fetotoxic effects
was originally based on three lindane feeding studies: Naishtein and Leibovich
(1971), Petrescu et al. (1974), and Earl et al. (1973).  At that time there
were no studies available to the Agency in which technical lindane was dosed
orally throughout the critical periods of organogenesis and in which the
results were reported in sufficient detail for a critical review.  In the PD
2/3, EPA concluded that the studies by Naishtein and Leibovich (1971)  and
Petrescu et al. (1974) had a number of flaws:which rendered them inadequate
to assess the reproductive effects of lindane.  However, at that time, Earl
et al. (1973) was still considered as unrebutted evidence of lindane's feto-
toxic effects.  In addition, several studies came to the Agency's attention
during the rebuttal period which influenced its decisions concerning fetotoxi-
city.  A discussion of these considerations is in PD 2/3 (EPA, 1980a,  pp. II-6
to 11-16).

EPA was unable to use the Earl study to determine a no observed effect
level (NOEL) and therefore did not use it to calculate margins of safety
(MOS) for fetotoxic effects.  The Agency did not use it because both doses
(15 and 7.5 mg/kg/day) were thought to cause adverse effects.   The Agency
did, however, use it in a qualitative sense in that the Earl et al. study
influenced its decision to set the maternal and fetotoxic NOEL at a level
below 7.5 mg/kg/day i.e., 5 mg/kg/day, based on the three pivotal oral terato-
genicity studies in rats (Palmer and Lovell, 1971), rabbits (Palmer and Neuff,
1971), and mice (Bauer and Frohberg, 1972 a and b).

      2.  Corrcnents on EPA's PD 2/3 Position

Comments submitted in response to PD 2/3 focused on two contentions:  1)  lindane
does not produce "selective" fetotoxic effects, because the effects occur in
laboratory animals only at or above doses which cause maternal toxicity, and 2)
the actual NOEL for fetal effects is four to six times higher than that used by
the Agency in PD 2/3.  Comments also stated that exposure estimates used by the
Agency were unrealistically high, and that if more realistic estimates had been
used, it would be clear that the margins of safety were ample (CIEL Volume I,
pages 42-54.)

NPDC (1983) contends that the Agency changed its analysis of lindane1s reproductive
and fetotoxic effects from PD 2/3 to PD 4.  NRDC asserts that several  oncogenicity
studies on lindane showed findings of testicular atrophy.  NRDC stated that the
EPA refused to rely on the study by Earl et al. (1973) and that EPA mischaracter-
ized the results reported by Khera et al. (1979).   Finally, NRDC is concerned
with EPA's draft PD 4 position that lindane causes fetal effects in test anijnals
only at or above doses which cause maternal toxicity.


                                    21

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At the SAP meetings of July  24  and August  13-14,  1980  (which followed issuance
of PD 2/3), questions were raised about whether lindane affects the adrenals,
pituitary, and gonads, as they  relate  to reproductive  or fetotoxic effects.
A question was also raised about the correlation  between reproductive effects
and adrenal ascorbic acid depletion.

      3.  EPA's  PD 4 Determination

In response to these concerns,  EPA conducted a thorough reevaluation of the
thirteen studies on the potential reproductive and fetal effects of lindane
(EPA, 1982a.)  These studies are sunmarized in Table 1.  Based on its
reevaluation of  these data,  EPA revises its position on the presumption
of fetotoxicity  and reproductive effects as follows (EPA, 1982a;  Memo, 1982b;
Memo, 1982e;  Memo, 1982g):

   a.  The Agency's concern  that lindane might cause adverse reproductive
effects, as distinguished from  fetal effects, has been successfully rebutted.
This conclusion  is based on  the fact that  testicular atrophy noted in the NCI
report (NCI, 1977) did not appear to be related to the treatment of the rats.
The NCI report noted that statistical  comparisons of treated with matched and
pooled controls  showed no significant  differences for  this effect.  Further,
there were no treatment related reductions in pregnancy rate or litter size
in the multigeneration reproduction study  in rats (Palmer et al., 1971).

   b.  After a thorough reevaluation of the Earl et al. (1973)  study, the
Agency only used the study to a limited extent in the assessment of fetotoxic
effects.  There  is no indication in the study whether  "average pups/litter"
includes live pups only or both live and stillborn pups.  In order to support
a conclusion regarding the toxicological significance of the rise in percent-
ages of stillborn pups, live pups per  litter should be presented.  The 7.5
mg/kg group (stillborn rate  - 22.7%) and the 15 mg/kg group (stillborn rate
= 17.9%) were close to the upper range of variation in untreated dogs (19%)
at the laboratory conducting the study and, therefore, there is no dose
response.  The results reported do not suggest that lindane has no potential
to cause fetotoxicity, but the  circumstances described here indicate that
the results are  equivocal.   Thus, the  Agency has not rejected the results of
Earl et al. but  considers the study of limited utility.  Further, the
fetotoxicity of  lindane has  been sufficiently studied  in several other properly
controlled studies, which allows a definitive scientific conclusion.

The Earl et al.  report did not  contain a description of maternal effects,
and in view of results from  other animal studies  (Palmer and Love 11,  1971;
Palmer and Neuff, 1971; Reno, 1976 a and b; and Bauer and Frohberg, 1972 a and
b) , data on maternal toxicity are necessary in the assessment of the results.

   c.  The results reported  by  Khera et al. (1979) do not indicate fetotoxic
effects below a dose level reported to cause slight maternal toxicity.  As
stated in PD 2/3, the increased number of  fetuses with anomalies in the mid-
dose group is unlikely to be compound  related.  Since there was no conccmittant
increase in the  number of litters with anomalous fetuses in that group and
no increased incidence of fetuses with anomalies was noted in the highest
dose tested.  Results reported  by Palmer and Lovell (1971) showed that
anomalies similar to those reported by Khera et al. (1979) were observed



                                    22

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at maternally toxic doses, and in view of the lack of increased effects
in the highest dose tested by Khera et al., the increased incidence of
affected fetuses is more likely to be a coincidental result.  Because of
these factors, the study was not used to set a NOEL.

   d.  The eight studies submitted in rebuttal to the Agency's PD 1 and
PD 2/3 followed conventional protocols and were reported in greater detail
than the three studies originally used by the Agency to support the presumption
of fetotoxicity.  In PD 2/3 the Agency rejected the rebuttal atteirpt and
noted that fetotoxic effects were observed in the submitted studies at or
near (both below and above) doses that caused maternal toxic effects.  In PD 2/3
the Agency also selected certain studies (Palmer and Lovell, 1971; Palmer
and Neuff, 1971; Bauer and Frohberg, 1972; Khera et al., 1979) for determining
a NOEL of 5 mgAg/day.

     For this PD 4, the Agency reevaluated the eight rebuttal studies and the   '
five other studies discussed in PD 2/3.  The Agency concluded that several of
these studies are adequate to confirm that fetal effects occur only at or above
doses that also cause maternal toxicity.  Fetal effects are not expected below
maternal toxicity levels because the one instance in which this may have
occured is believed to have been coincidental (see discussion of Khera et al.
above) .  The Agency also reconfirmed the NOEL of 5 mgAg/day based on the same
studies cited above in PD 2/3, except for Khera et al. (due to its limitations
discussed above).  The value of 5 mgAg/day as a NOEL is consistent with
other toxicity data based on subchronic dosing of lindane.  From these same
four studies (Palmer and Lovell, 1971; Palmer and Neuff, 1971; Bauer and
Frohberg, 1972 a and b), the  NOEL for fetal effects (in the presence of
maternal toxic effects) is 10 mgAg/day.

   e.  CIEL submitted to EPA a thorough response to the Scientific Advisory Panel's
concern that lindane might affect the reproductive glands.  Their conclusions,
with which EPA agrees, are that:

0 Multi-generation, chronic and subchronic studies in the rat and in.
  dogs have failed to show any effects on adrenal, testicular, or ovary
  weights (absolute, as well as relative, weights).  No findings have indicated
  effects on adrenals or gonads which could be related to reproductive or
  fetotoxic effects.

0 Higher urinary excretion of Vitamin C was observed in the studies by Trivonva
  et al. (1970), Petrescu et al. (1974), and Naishtein and Leibovich (1971).
  This is a frequent side effect of enzyme induction in rodents.  There was
 '• no evidence of a reduction of ascorbic acid, but there was evidence of increased
  synthesis of ascorbic acid in the liver of test rats.

In conclusion: EPA's reevaluation finds that lindane (a) does not cause
reproductive effects, but (b) does cause adverse fetal effects in test animals,
but only at or above doses which also cause general toxic effects in the
mother.  It is not possible to determine whether these effects are "selective"
                                    23

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(direct) fetotoxic effects, or whether  they are  indirect effects which are
caused by the effects on maternal animals.  Nonetheless, the Agency has a
responsibility to protect  fetuses from  possible  adverse effects of lindane,
whether these effects arise from selective and direct activity on the fetus,
or whether they arise indirectly through  toxic effects on the mother. From a
regulatory and practical standpoint,  the  data indicate that protecting mothers
from acute to>{ic effects will simultaneously protect fetuses from possible
adverse effects. Therefore, the regulatory decision for fetal effects is
based on both the NOEL  for maternal toxicity and the NOEL for fetotoxicity.
The data indicate that  this will be adequate to  ensure that neither general
nor fetal toxicity (direct or indirect) will occur (EPA, 1982a; Memo, 1982b;
Memo, 1982e; Memo, 1982g).

This NOEL (5 mg/kg/day) is the same dose  level used in the PD 2/3 as a NOEL
for fetotoxicity.  The  only difference  between this PD 4 position and the
PD 2/3 position on this issue, is that  by referring to this dose level as a
NOEL for general toxic  effects, the Agency is acknowledging that there is no
persuasive evidence for a  selective effect on fetuses at levels that do not
produce general toxicity.  The NOEL for fetotoxicity is apparently 10 mg/kg,
but this has little regulatory significance, since the 5 mg/kg general toxicity
NOEL would be applied to all use situations for  which the fetotoxicity NOEL
would be appropriate.
                                    24

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                                                                               TAnt.E 2

                                                             COMPARISON OF NO ORfiERVEn EFFECT LEVELS FDR
                                                                     MATERNAL AMO FETAL EFFECTS
U1
Species
i
Mouse
Pig
Dog
Rat
Rat
Rat
Rabbit
Rat
Rat
Rat
Rabbit
Rat
Route of
Administration
Oral (gavaga)
• Dietary
Dietary
Oral (gavaga)
Oral (gavaga)
Oral (gavaga )
Oral (gavaga)
Dietary
Dietary
Subcutaneous
Subcutaneous
**
nr»EL for
Maternal effects
30 mgAg/day
>20 mgAg/day
'
*
*
5 mgAg/day
5 mgAg/day
>5 mgAg/day
*
15 mgAg/day
5 mgAg/day
*
NOEL for Ratio Fatal NML
Fetal effects Maternal Nnei,
30 mgAg/day
>20 mgAg/day
*
. •
*
10 mgAg/day
10 mgAg/day
>5 mgAg/day
*
>30 mgAg/day
5 mgAg/day
*
1
*•
*
•
*
2
2
• •
*
>2
1
•
to
References
Bauer and Frohborg, 1972a
and 1972h
Duee et al., 1975
Earl et al., 1973 ***
Khara et al., 1979
Naiahtein. and Leibovich,-
1971
Palmer and Lovell, 1971
Palmar and Neuff, 1971 '
Palmar et al., 1972
Petrescu et al., 1974
Reno, 1976a
Reno, 1976b
' Trivonva et al., 1970 ***
                  •Not oatermlnable because of  insufficient  Information to evaluate study.

                 **Not determlnable because dosages were not high enough to cauflo fetal or maternal toxlclty.
                 *** Of  limited or no regulatory significance.

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III.   OTHER POSSIBLE ADVERSE EFFECTS
               26

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   A.  £?A's Concern Regarding Acute & Subacute Hazards to Humans and
       Danestic Animals

      1.  EPA's PD 2/3 Position
The Agency based its original concern regarding the acute effects of lindane
on numerous studies in humans and animals which show that lindane causes
symptoms of acute and subacute toxicity typical of central nervous system  (CNS)
stimulation (PD 2/3, pp. 11-22 to 11-31, and pp. 11-77 to 11-79.)

In PD. 2/3, EPA determined an' approximate no-effect level (NOEL) of 2.5
mg/kg/day, based on Hayes (1963), and supported by the results of Desi  (1974).  ••
The following points were emphasized:

   - effects at low dosage levels may be reversible;
   - subtle, sub-symptonatic effects may occur below 2.5 mg/kg/day, and these
     changes could affect the functional efficiency of nerve transmission;
   - among adults there may be a high degree of variation in sensitivity to the
     CMS effects of lindane; and                                               *
   - sensitivity in the young may be considerably greater than that of adults


Risk to humans was evaluated by comparing the 2.5 rag/kg/day NOEL with the
highest estimated daily exposure for each use of lindane. The resultant margins
of safety (MDS) for adults may be found in the PD 2/3 (pages I1-74 and 11-75.)
There was not enough information to calculate separate margins of safety for
children, but they are assumed to be lower than those estimated for adults.


Studies illustrating the types of effects lindane may cause at various doses
are summarized below (EPA, 1982a):

At low-doses, lindane produces apparently reversible toxicolcgical effects.
At 3 mg/kg/day, lindane taken orally caused temporary dizziness in humans
(Hayes, 1963).  Similarly, low doses (2.5 mg/kg/day given for 22 to 40 days)
were reported to cause decreased learning ability and affected operant behavior
in rats (Desi, 1974). (Note that, for the reasons cited below, the Desi and
Hayes studies have not been independently relied upon for estimating a NOEL
in the PD 4.)  Decreased food consumption was observed at 5 mg/kg/day in
Palmer and Neuff, 1971; at 5 mg/kg/day in Reno, 1976b;  at 10 mg/kg/day in
Palmer and Lovell, 1971; and at 30 mgAg/day in Reno, 1976a. Body weight
IQSS was observed at 5 mg/kg/day in Palmer and Neuff, 1971; and at 10 nig/kg/day
in Palmer and Lovell, 1971.

Medium-dose studies showed more serious, possibly non—reversible effects
such as nerve impairment. Schwarz and Kuschowitz (1968)  showed that lindane
slowed the process of excitation in in vivo experiments on the retina of
frogs.   These results are consistent with the in vitro results in rat nerve
tissue (White and Larrabee, 1973), which showed that lindane inhibits
transmission of nerve impulses at synapses in ganglia.   Dellamagne et al.
(1950)  also reported synaptic nerve danage in dcgs given repeated intraperitoneal
injections of 10 to 30 mg/kg for up to 44 days.
                                   27

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 At high doses, lindane is capable of  inducing convulsions and death.  Hanig et
 al. (1976) produced convulsions with doses of 60 to 120 mg lindane per kg body
 weight, applied to rabbits' skin following shaving, depilation, and stripping.
 The same effects were seen when doses of 2.4 to 11.5 mg/kg, via the carotid
 artery, were given to dogs, cockerels, and rats (Litterst and Miller, 1975;
 St. Oner, 1971).


       2.  Comments on EPA1 s PD 2/3 Position, & the Agency's PD 4 Determination

          a.  Basis for calculating the NOEL

             i.  EPA's PD 2/3 Position

 CIEL  contended that the Hayes (1963) data should not have been used by the
 Agency to calculate an acute effects MDS, because they are based upon subacute
 rather than acute exposure to lindane. The human studies referred to in PD 2/3
 (Hayes et al., 1963) were considered by rebutters to lack specific information
 necessary for interpretation of reported observations.  According to conroentors,
 these deficiencies included, no references of sources for the data presented,
 no information on body weights or health status of the "patients" receiving
 lindane, no information about the size of the test groups and no inclusion of
 a placebo dosed or untreated group.  Rebutters also contended that comparisons
 of single with split dosage regimens is inappropriate and further, that inade-*
 quate reporting of details rendered the human data useless for purposes of
 establishing a no-observed effect level. CIEL also stated'that thirty years
 of clinical use of lindane suggest that the NOEL is considerably higher than
 2.5 mgAg/day, although CIEL did not attempt to derive a NOEL fron the clinical
 data available (CIEL Volume I, pages 54-55).  NRDC (1983) objects to the
 general toxicity NOEL of 5 mg/kg/day because "no standard toxicicological
 studies exist" and because a 32-week study on beagle dogs indicated toxic
 effects at 5 mg/kg/day.

             ii.  EPA's PD 4 Response

 The Agency and carmentors agree that lindane causes acute effects.  Upon review
 of the data reported by Hayes et al. (1963), the Agency acknowledges the
 deficiencies noted by carmentors.  Although the deficiencies preclude use of
 the study results for calculating margins of safety, the Hayes et al.  data
 support the Agency's previous conclusion (in PD 2/3) that humans and animals,
 with similar lindane exposures are likely to exhibit similar signs of toxicity.

 In vie// of considerations described in section Ill.l.b.iii.  below, and results
 of studies described in section II above, a NOEL of 5 mg/kg/day can be established
 for lindane toxicity.

      In its conment about documentation to support the statements about human
"experience with lindane, the NRDC did not discuss the citations on page 20 of
 the February draft PD-4.  Citations by the Agency included reports by Kramer
 et al. (1980), Morgan et al. (1980), Ginsberg et al. (1977), Halpern et al.  (1950),
 and Woolridge (1948).  These references support the conclusion that a 5 mg/kg
 NOEL is likely to be appropriate in assessing the acute hazards of lindane.

      The 32-week dog study mentioned by the NRDC,  characterized potential
 hazards that are more likely to be associated with longer exposure periods.
 The teratcgenicity studies are more comparable to shorter exposures,  and
 thus they are more appropriate to an assessment of potential acute hazards.
                                  28

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            iii.  EPA's PD 4 Position

The studies reviewed by the Agency for establishing a NOEL for lindane with
respect to the CMS stimulation effects are consistent with Hayes (1963) and
Desi (1974), although neither of these two studies is sufficient to independently
establish a NOEL (as explained above).

The no effect level for general toxicity found in the reproductive studies
was 5 mg/kg/day.  Reversible CNS effects have also been noted in Hayes (1963),
Desi (1974), and Joy et al. (1982) at 3, 2.5, and less than 5 mg/kg/day,
respectively.  Since many of the studies investigating lindane's neurological
effects are specific in nature (e.g., Joy et al., 1982; Desi, 1974), they are  .
more likely to establish lower no-effect levels than the more generalized,
conventional subchronic toxicity tests.  Such no-effect levels are of
questionable toxicological significance because of the specific and reversible
nature of the effects and the studies were not designed to determine the toxi-
cological significance of such effects.
Clinical evidence fron lindane's human pharmaceutical uses suggests that
exposures somewhat higher than 5 mg/kg/day do not usually
result in acute neurotoxic symptcms (Kramer et al., 1980; Morgan et al.,
1980; Ginsberg; et al., 1977; Halpern et al.i, 1950; Wcolridge, 1948).          »
Also, the literature on lindane suggest that 1.25 mg/kg/day is the approximate
NOEL for liver enlargement, when exposure is chronic (Memo, 1982c).
These factors as well as those described in section b., below, led the Agency
to conclude that 5 mg/kg/day is an appropriate no-effect level for the
reversible CNS effects.
         b.  The Nature of Effects On the Nervous System

            i.  EPA's PD 2/3 Position

The Agency described the toxic effects associated with a range of dosage levels
(see section A. 1., above).  In addition, the Agency cited data (Koransky and
Ullberg, 1964) which indicated that lindane accumulates in the white matter
of the brain of laboratory rats.  This observation was used by the Agency to
support the conclusion that lindane adversely effects the central nervous
system (CNS).
                                 29

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             ii.  Garments  en EPA's  PD_ 2/3  Position

CIEL contested EPA's  statement in the PD 2/3  that lindane has an affinity
for white nerve  tissue,  "where it accumulates and causes symptoms of acute
and subacute poisoning...."   They pointed  out that in PD 2/3, EPA incorrectly
reported that the Koransky and Ullberg (1964)  study found the gamma iscmer
of hexachlorocyclohexane (lindane)  to accumulate exclusively in the brain
structures containing white  matter.   In addition, rebutters stated that there
is no evidence to suggest  that lindane causes delayed adverse effects on the
nervous system ( CIEL  Volume  I , pp 56-59 ) .

The effects  characterized  by existing data suggest early warning signs of tcxicity
according to rebutters.  Rebutters  contended  that many of the studies do not
characterize the toxicolcgical significance of the specific effects observed.
One study involved  in vitro  investigations (White and Larabee, 1973) while
others (Dellamagne, 1950;  St. Oner,  1971;  Litterst and Miller, 1975; and
Koransky and Ullberg, 1964)  used methods of administration (via injection or
infusion into the carotid  artery) which are not relevant to routes of human
exposure.  Two experiments (Hanig et al. ,  1976;  and Schwartz and Kaschcwitz,
1968) did not establish  no-effect levels.   The studies of lindane 's effects
on behavior  in rats (Desi, 1974)  were described by rebutters as inconsistent
and not dose-related.
             iii. The Agency's PD 4  Response
SPA acknowledges  that  it  incorrectly reported  the results of the Koransky and
allfcerg (1964) study.  The study reported results for  the alpha but not the
gamma (lindane) iscmer of hexachlorocyclohexane.   The  alpha isctner, which is
known to have approximately the same lipcphilicity as  lindane, was reported
to accumulate exclusively in brain  structures  containing white matter.
However, these findings were not reported in detail and the study cannot be
evaluated for its accuracy.

Sonewhat different  results were obtained in the dog by Litterst and Miller
(1975), who analyzed twelve regions of  the brain  for lindane concentrations.
All regions sampled had approximately equal concentrations of lindane in
spite of different  proportions  of white to grey matter.

As noted above, many of the studies used inappropriate routes of administration.
They investigate  specific neurological  effects without determining the toxicc—
logical significance of the observed effects.
                                    30

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 These deficiencies limit the value of these studies for purposes of establish-
 ing a no-effect level.

 The Agency re-evaluated the studies reported by Desi (1975) and agrees that
 there are inconsistencies in the report.  However, the results suggest that lindane
 affects neurcmotor function (Reiter, 1982) which is consistent with _in vitro
 studies in rats (White and Larabee, 1973) and the study on the frog retina
 (Schwartz and Kaschcwitz, 1968).

 Due to inconsistencies such as inappropriate statistical analyses, the possibility
 exists that variables other than lindane may have affected results, and the
 apparent reversibility of lindane's effect on behavior of test animals (Reiter,
 1982), the Desi study cannot be used to demonstrate no-effect levels for
 general neurological effects (see discussion below).

 Subsequent to the publication of PD 2/3, a study by Joy et al. (1982) came to
 the Agency's attention.  The study showed that 3 and 10 mg/kg/day doses
 (administered by gavage for 5 consecutive days in rats) increased the reactivity
 of the brain of rats to electrical stimuli (kindling). There were no effects
 on behavior noted by the authors.  One mg/kg/day had no apparent effect.

 Since the electrical stimuli were'administered through electrodes implanted
 in the brains of the rats, the study does not characterize the toxicolcgical
 significance of lindane's effects (Zendzian, 1982).

 As indicated by rebutters and in the preceding discussion, the animal studies
 evaluated specific aspects of lindane's neurological effects over a wide
 range of doses.  IXie to the specific nature of these studies, a no-effect •
 level derived fron them is likely to be lower than that found in
 standard, less specific, toxicolcgical studies normally used to evaluate a
 chemical.  The lowest no-effect level of 1 mg/kg/day suggested by results
 from Joy et al. (1982), is less than the 5 mgAg/day NOEL found in the
 reproduction and teratology studies listed in Table 1.  In light of the difficulties
 described earlier regarding the studies by Desi (1975) and Joy et al. (1982),
 the studies are useful only as supportive evidence for determination of a
 no-effect level.

 As noted by rebutters, the effects described by Desi (1975) are apparently
 reversible (Reiter, 1982).  Joy et al. (1982)  cited other studies that suggest
 the need for additional experiments to determine whether the CNS effects  they
 observed are reversible (Zendzian,  1982).  Based on these considerations, the
 Agency agrees that the neurological signs observed at lew doses can best be
 interpreted as warning signs of lindane intoxication.

      NRDC (1983) objected to the Agency's determination of the 5.0 mg/kg/day
'NOEL for general toxicity.  NRDC was also concerned about the "lack of standard
 toxicolcgical data."  Finally, NRDC asserted that the 5.0 mgAg/day NOEL "will
 justify higher exposures to children."  As discussed above, the 5.0 mg/kg/day
 NOEL was based on studies where irreversible effects were observed.  Studies
 where reversible effects were observed were not considered sufficient for
 establishing a NOEL.  The Agency does not believe that there is a lack of
 toxicolcgical data with which to establish a NOEL.   Regardless of these technical   *
 issues, it should be noted that the acute effects observed in the available studies
 have not and do not meet an RPAR criterion, and further analysis is not necessary.
                                 31

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         c.  Sensitivity of Children  to Lindane

             i.  Garments on SPA's ?D 2/3 Position

Recut-ers disputed the Agency's concern that children are more sensitive to the
toxic effects of lindane than adults,- stating that "the Agency failed to
consider that enhanced sensitivity of children is a problem cannon to all
chemicals."  Furthermore, they stated that the high incidence of lindane
poisonings resulted fron accidental misuse, such as ingesticn by children,
rather than from special sensitivity  of children to lindane's effects.
However, the Scientific Advisory Panel's review stated that "The Panel agrees
with EPA that lindane is substantially more toxic to young than adults in
both humans and domestic animals..."
                                   32

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            ii.  EPA's PD 4 Response

Because of these different interpretations of the data, EPA carefully
reevaluated the issue of special child sensitivity (EPA, 1982a, pp. 29-30,
32-37, and 46-47; EPA, 1983a).  The results are as follows:

Equivalent dosages (on a surface area basis) of lindane, applied to
adults and children,  produce a greater mg/kg body weight dose in children.
This is consistent with the fact that children have a higher ratio of
surface area to body weight than do adults.  Other factors which theoretically
enhance toxicity to children of many chemicals are greater skin permeability
in children, and the  lack of mature hepatic conjugating enzymes for
detoxification and excretion.  The best animal study to date (Solomon et
al., 1971) does not suggest differences between newborns and adults with
respect to lindane absorption.  The doses used were relatively low (0.5-
2 mg/kg) and in a range that is not associated with definitive toxic
effects (see Section III. A. 2. above).  Therefore, the study cannot
be used to rule out the possibility of differences in sensitivity.
                                                       i
The other animal studies reviewed have flaws which make them less useful for
evaluating childhood  sensitivity. In Hanig et al. (1976), the results may
have been compromised by the fact that the animals were subjected to severe
treatment of their skin (EPA, 1982a).  Furthermore, the results are of
questionable reliability because of the very small test groups used, the
lack of a vehicle control, and the lack of differentiation between the
surface-to-body-weight ratio in weanlings compared to adults.  However,
qualitative effects were noted in weanlings which were absent in the
adult animals.  In Mohrmann and Weisberger (1977), the doses were lower
than those used in the Hanig study, and no effects were seen, so compari-
son of the younger to the older groups is not appropriate.

The Agency has also carefully reviewed the clinical reports of lindane
intoxication, many of which involved children.  There were significant
differences in the clinical observational procedures, differences in
integrity of the skin surfaces of the patients, and differences in the
conditions of exposure.  These variations preclude the use of such case
reports in any quantitative way, but support the Agency's concern that
children may be more  susceptible to toxic effects from exposure to
lindane.  However, none of these data show a distinctive and peculiar response
by different age groups, other than the generally established sensitivity
of the young to intoxication, as discussed above.  Special warnings
concerning exposure of children, and child resistant packaging where
appropriate, are imposed on lindane products.  The Agency also notes
that with these use precautions, exposure of children to lindane is likely
to be far less from pesticidal use than from the pharmaceutical use
for treatment of lice and mites.  The pharmaceutical use is regulated
by the Food and Drug  Administration under the Federal Food, Drug,
and Cosmetic Act.
                                     33

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   3.   Possible  Association Between Lindane and Blood  Dyscrasias

      1.  EPA's PD 2/3  Position

In PD 2/3, EPA stated that available data on lindane were  not sufficient to
establish a cause-effect relationship between lindane and  blood dyscrasias.
However, the Agency noted that two epidemiologic studies were in progress at
the time of publication of the PD 2/3:  one in Iowa, and the other in Hawaii
(PD 2/3, pages 11-21 and 11-22.)


      2.  Carrnents on EPA's PD 2/3 Position

The FIFRA Scientific Advisory Panel,  in its comments on the Agency's PD 2/3
position, stated:  "The  Panel agrees with EPA that... chronic exposure can
sometimes result  in disastrous blood dyscrasias." However, this was a
misstatement of the Agency's actual position,  which was, and still is, that
there is not sufficient information to establish'a cause-effect relationship
between lindane and blood dyscrasias.
                                                                              »
NEDC (1983) urges  "the  Agency to  consider the results of the Hawaiian
epidemiolcgical study currently underway regarding this hazard...."  The
Agency has done so,  and in discussion under III.B.3./ below, has found no
evidence to alter  the original PD 2/3 conclusion.

      3. EPA's PD  4  Position

The Iowa study (Morgan,  1980)  surveyed' 215 households in Iowa and Illinois
where lindane vaporizers were used.  This population was chosen because
vaporizer use resulted  in continuous,  high levels of exposure. The stated
intent was to discover  symptoms which would suggest lindane-related injury.

The investigators  reported no correlation between lindane  blood levels and the
occurrence of adverse hematologic effects.  Blood levels of lindane did correlate
significantly with age,  and so did several hematology and  biochemical
measurements, but  it was not known whether these resulted  from an actual
lindane-related effect,' or fron confounding environmental  factors or
methodological variations.  The most important  result was that no obvious cases
of anemia or blood dyscrasias were found in any  of the  individuals routinely
exposed to lindane.

The Agency has received the first draft of the Hawaii study.  The purpose of
the study has been to collect, case histories of  people  with blood dyscrasias
in Hawaii and to attempt to correlate these with past exposures to pesticides.
Out of 96 case histories of individuals with various blood dyscrasias (includ-
ing aplastic anemia), only 2 reported any contact with  lindane.  No statistically
significant association of exposure to lindane with the incidence of blood
dyscrasias was seen.
                                 34

-------
One other study (Kramer et al., 1980) in humans, does not establish a cause-
effect relationship between lindane and blood dyscrasias because the lack  of
£ollcw-uc and complete medical histories prevents  interpretation of the  results
(EPA, 1982a).

In conclusion, the Agency received no new data that would alter the previous
position. The Iowa epidemiology study discussed above similarly provides no
information to establish a cause-effect relationship between lindane and
bleed dyscrasias.

   C.  Acute Toxicity to Aquatic Wildlife     '

      1.  EPA's PD 2/3 Position
The Agency's original presumption of acute toxicity to aquatic organisms was
withdrawn in the PD 2/3, because no lindane products were registered for
aquatic uses.  However, the Agency stated concern about the possibilities of
drift or runoff should any non-aquatic lindane product be misused, since
lindane is "very highly toxic" to aquatic wildlife (its LCso is less than
0.1 ppm; see Henderson et al., 1959; Eisler, 1970).                        .


      2.  Comments Received, and SPA's PD-4 Final Position

The Agency received two comments on this issue. One was a series of
letters (3000/lOc, t!04-109) expressing concern that lindane was killing the
insect populations of the VSiite Clay River (in Pennsylvania and Delaware),
thereby adversely affecting fish populations in the river. Several possible
sources of the lindane contamination were cited, but there was no evidence with
which to determine the exact source or sources.  However, the Agency has since
received reports from the two affected states, which have been monitoring
lindane levels in the water since September, 1978. Of 27 readings, all but four
have been below one-tenth the acute LC 50 value (.2 parts per billion for the
most sensitive species, the brown trout.) The four values which exceeded one-
tenth the acute LC 50 value occurred between September and December 1978, and
have never occurred since.  In addition, readings on fish residues have been
                                    35

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consistently  lew (Memo,  1982h.)

The U.S. Department  of Agriculture advised EPA that aerial spraying of lindane
for forestry  use would be  unadvisable  cue  to the possibility of runoff and
drift  (see Appendix  I).

Since  lindane is very  highly toxic to  aquatic organisms, but is not registered
for direct aquatic application,  EPA is chiefly concerned about avoiding
misuse and/or application  practices which  could result  in drift or runoff.
Therefore, although  the  PD 2/3 withdrew the presumption of acute toxicity to
aquatic organisms, the Agency has  taken this issue  into account in its
risk-benefit  analysis, and will  require label prohibitions against practices
which  cculd result in  significant  amounts  of drift  or runoff, such as improper
disposal of dips, and  aerial application.


   D.  Possible  Population Reductions  in Non-target Avian Species

No new evidence  was  submitted to the Agency since the Pl>2/3. The Agency
maintains its position that there  are  insufficient  data to initiate a
rebuttable presumption on  the basis of population reductions in non-target
avian  scecies.
   E.  Possible  Isonerization

In the PD 2/3, EPA concluded  that  isonerization  of  lindane had not been
established; this was a  concern because other  iscroers of BHC are cnccgenic in
mice.

A 56-day feeding study in  rats was submitted to  the Agency since issuance of
the PD 2/3, showing  that no significant iscmerization of lindane to the
carcinogenic alpha or beta iscmers of BHC occurs in rats above the limit
of detection (Burkoth and  Paul, 1981; confidential  rebuttal #94-D).  The
study used an appropriate  protocol,  sufficient numbers of control and treated
male and female  rats, and  appropriate (maximal)  doses administered orally
(gavage).  The study was capable of  detecting  very  low percentages of
iscmerizaticn, tut no indication of  significant  isonerization to the alpha
or beta iscmers  of BHC was found.

Two limitations  of the data are that the study was  not long enough to detect
possible long-tenn bicaccumulaticn of iscmers, and  that isonerization in
rats has only limited relevance to the situation in mice, the only species
in which carcinogenic effects have been observed.   However, these limitations
are minor and do not change EPA's  position  that  isomerization of lindane has
not been established (Memo, 1982a).

   F.  General Toxicity  of Lindane

The toxicity of  lindane  has been the subject of  many studies.  Liver toxicity,
resulting in increased liver  weight  and hepatic  lesions, is characteristic
of lindane.  The acceptable daily  intake for lindane was set from a NOEL
                                    36

-------
of 1.6 mg/kg/day frcm a 2 year chronic feeding study in dogs (VHO,  1974).
In a 2 year feeding study in rats, levels at and above 2.5 mg/kg/day
produced liver weight increases and hypertrophy.  The NOEL in this  study
was 25 ppm or 1.25 mg/kg/day (Truhaut, 1954; CAG, 1979).

A recently submitted 3 month, subchronic oral feeding study in rats has been
cursorily reviewed by the Agency (Locke, 6/17/83).  The NOEL was 4  ppm or
approximately 0.3 mg/kg/day.  At the next highest dose (20 ppm in the diet),
kidney damage, which was not reversible after a 6 week recovery period, was
evident in both males and females.

Based on the results of this study, the Agency will give high priority to
the development of a Registration Standard for lindane.  In order not to
delay the implementation of the regulatory measures resulting frcm  the RPAR
review of lindane, it was decided to issue.this FD 4 at this time.   As
part of the Registration Standard review, the Agency will perform a
thorough evaluation of lindane's general toxic effects, including a review
of the complete chronic and sub chronic data base.
                                   37

-------
   IV.  EXPOSURE
•__._. 38

-------
   A._ Non-dietary exposure to lindane

Detailed discussions of many lindane uses are provided in the
exposure analysis narrative, contained in Appendix III.  In overview,
differences between the FD 2/3 and PD 4 exposure estimates are due to the
following:

1. In PD 4, EPA uses exposure information and studies which were not available
when the PD 2/3 was published. Comments received on the PD 2/3 exposure
analysis were generally of excellent quality, and provide the Agency with
better, more detailed information which enables a more informed regulatory
decision.  The Agency also uses recently published studies on similar chemicals,
where they provide better surrogate data for making exposure assumptions.
For example, the Agency uses a more appropriate study for estimating exposure
to applicators who use back-pack sprayers (Appendix III.)

2. In PD 4, EPA considers cccnmonly accepted use practices, rather than the
theoretical worst-case use practices as were assumed in PD 2/3, because
better data are available to replace the previous theoretical assumptions.
ranges of estimates are presented for those uses where there was enough
information to do so.                               :

3. In PD 4, EPA acknowledges those uses in which protective clothing is
already routinely worn therefore eliminating risk assessment when protective
clothing is not worn.  This information helped the Agency to determine that
the protective clothing requirements under consideration will not require changes
in those use practices.  It also assured the agency that imposing protective
clothing requirements for other uses will be effective in reducing risks;

Assumptions regarding the rate at which lindane is dermally absorbed are
the same in PD 4 as in PD 2/3.  Liquids are assumed to be absorbed 10%,
and dusts 1% (Memo, 1982f).

Generally, the considerations noted above (more detailed information for
specific uses and assumptions concerning actual use practices, including
protective clothing where appropriate)  reduce the levels of exposure
estimated in PD 4 from those estimated in PD 2/3 for most use patterns.
The specifics of each assumption used in this document, and the reasons
for any modificatioas of the PD 2/3 assumptions, are presented, in detail,
in the Exposure Assessment (Appendix III).

Lindane has so many uses that exposure estimates could only be calculated for
a representative subset, which,  however, accounts for most identifiable usage
of lindane.  Because of this, and to provide a framework'for regulating new
uses in the future, the Agency has categorized the results of the exposure
analysis in PD 4 according to the application method used. In the case of
lindane, application methods correlate highly with risk, so categorizing
uses in this way provides a rational regulatory perspective.

Exposure situations (excluding dietary exposure) are divided into the following
                                   39

-------
      categories  (forestry/  homeowner ornamentals, and foliar applications
      to Christmas  trees)
   3. Structural  treatments  (subterranean  termites, powder post beetles)
   4. Dip applications  (hardwood  logs and  lumber, livestock dips, dog
      dips and shampoos)
   5. Enclosed area sprays  (moth  sprays, uninhabited building and storage
      bin sprays)
   6. Dust applications  (seed  treatment, dog dusts)
   7. Selow-shoulder spray applications  (cucurbits)
   8. Pre-plant soil applications (pineapples, sugar cane*)
   9. Other household products (flea collars, shelf paper, household sprays).

Comparison of FD  2/3 with FD 4 annual exposure estimates for each use are
presented in Table 3.  Estimated  daily exposures are presented in Table 4.

A narrative describing the details of the  Agency's final non-dietary exposure
analysis may be found in Appendix III (EPA 1982b). It provides summaries of
EPA's PD 2/3 analyses, comments received regarding those analyses, revised
assumptions, and  estimates of  exposure for each of the lindane uses. Tables
showing details of  the PD 4  calculations are not reprinted here, but are
available upon request  (EPA  1982b.)

     NPDC (1983)  charges that  the estimated exposures to lindane have been
substantially decreased between PD 2/3 and PD 4; that the studies upon
which these changes were based are not generally adequate or relevant
(and therefore, new exposure studies should be required); that assumptions
were based on comments rather  than new evidence; and that the reduced
exposure estimates  "artificially  reduced the true risks of lindane use...."
The agency disagrees with NRDC's  assessment of the seven studies received
in response to PD 2/3.  These  have been evaluated and found to be adequate
for exposure estimates and certainly are more sound than scene of the
theoretical worst case assumptions which were used in PD 2/3.  Any changes
in assumptions, such as end-use dilutions, were based on ccmments and
subsequent confirmation from pesticide labels, conversations with experts
outside the Agency, etc.  For  the record,  19 of 29 exposures (not 23 of
29) were reduced, 2 remained the  same, and 8 increased.  The Agency
rejects the contention that  exposure estimates were "artificially" reduced
and stands by its estimates  as more accurate and realistic.
                                   40
   Sugar cane  is not a currently registered use of lindane, but its use
   on sugar cane has been allowed as  a Section 18 emergency use.

-------
                                                                TAIILB  3

             USE UV USB SUMMARY Of  BSTIMATED ANIIUAI. BXI'OSUHIi* (HG/KtAH |i/ TO LIHDAHEl	HES.UI/fg.Of VU  I/ i COMPARED HI Til  Pu  4

Pp 2/3
WITHOUT PROTECT I VK CLOTH INO
Deraal-i' Respiratory
ABOVE SHOULDER SPRAYS
AIR DLAST or
POWER HAND GUH
OHHAKEHTALS 90-3600 0.5-22
(commercial)
AVOCADOS 800 1.6
PtXV.iiS 395 0.8
LIVESTOCK 6.5 0.04
ABOVE-SHOULDER SPRAYS
BACKPACK or
HAND PRESSURE
ORHAMEHTALS 30 0.18
(homeowner a)
rORESTKY 2400 16
CHRISTMAS TREES 810 2.7
(foliar)
CRAWL SPACE TREATMENTS
STRUCTURES
Applicators 5600-11200 20-40
Residents 4 / 60
' 	
PD 4
KITUOUT PROTECTIVE ClvOTUIHU KITH PROTECTIVE CLOTH IUG
Uermal-i' Respiratory Denial^/ Respiratory-/

/

H/AJ?/ H/A 48 0.24
320 0.6 64 0.6
160 0.3 32 0.3
H/A H/A 7.9 0.01



3.6 0.02 0.7 0.02
H/A H/A 56 0.3
H/A H/A 5.4 0.02

H/A H/A .0.5 0.3
1.4 H/A H/A
(once in 10 yra)
1.  Dermal exposure estimate la not multiplied by skin absorption factor.  This la factored Into rlak eatinatea by Toxicology Branch.
2.  Where respiratory values in the 'with protective clothing* column do not differ from the respiratory estimate "without protective
    clothing*, it is because respiratory protection la not required and lisa not been factored In.
3.  H/A - Hot Applicable
4.  — - negligible
5.  IJD - Hot Determined
                                                                                41

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                                                          TAULB 3 (Continued)

              USB BY USE SUMMARY  OP ESTIMATED ANNUAL BXPOSUIlfe  (HG/YBAHli/  TO l.lHDAHKl  HBSUI.TU OF  Pl>  2/1  COMPARED  WIT II  VU;  4

PU 2/1
WITUOUT PROTECT I VB CLOTHING WITHOUT PROT8CTIVB CLOTH I HO
Deraiali/ Respiratory Uermal-i/ Respiratory
DIPS
UAHDWOOD3 32,000 ISO ll/fc H/A
DOG DIPS
Applicator* 0.3 -- 11.1
Poet-treatnont -- 8.9xlO~s to — 0.03
Exposure . J.7«10"*
ooa SIIAHPOOS
Appllcatora 51.4 — 10.5 :
Poat-tceatnont — 0.03-0.1 — 0.02
Exposure
ENC1X3SKU AHEA SPRAYS
MOTll SPRAYS
Applicator a -- 0.18 3.3 2.3
Enployoea — 1.4 — 1.4
FUMIGATION DEVICES — 149 — 6.4
UNINHABITED BUILDING — 18.7 ' 0.5 0.02
i STORAGE BIN SPRAYS

PD 4
WITH PnOTECTIVt CLOTHING
I)erua)i/ Respiratory^/
16.8
2
N/A H/A
2.1
M/A N/A

0.7 2.3
N/A N/A
N/A N/A
0.1 0.02
1.  Dermal exposure outlraato la not multiplied by akin absorption factor.   Tlila la factored into risk  ustlmatas by Toxicology Branch.
2.  Hhero rebplratory values In the "with protective clothing*  column do not  differ  from th« respiratory  eatlotato 'without  protective
    clothing*. It la because respiratory protection is not required and has not been factored in.
3.  N/A - Not Applicable                          ,,„...
4.  — • negligible
*>.  ND - Hot Deternlned
                                                                              42

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                                                          TAULK 3 (Continued)




              USB BY USB SUHHAHt Of  ESTIMATED  AIIIIUAI.  KXPOSUftB  (Ma/YEAIl)-^/ Tt    AllAHB ( IIBUUl.Tfl Of PD 2/3 COMPARED H1TH t>U 4

PD 2/3
WITHOUT PROTECTIVE CLOTHING
Dernali/ Respiratory
DUSTS
SEED TREATMENT
Applicator a 306 7.7
Seed Sowing HoV NO
DOG DUSTS
Applicator* 191 0.1
Post-treatment — 2.53
Exposure
BELOH SHOULDER SPRAYS
CUCURBITS 4.7 0.01
CHRISTMAS TREES 87/27 1.8/0.2
iacump/slaah)
iijJKCT.'.BLS OH PREPLAN!
G;;:L A.TLI CATIONS f
PINEAPPLES — 7 X 10"'
HOUSEHOLD PRODUCTS (OfHEH)
PLEA COLLARS — 0.045
SHELF PAPER — 5
HOUSEHOLD SPRAYS
Applicators — 1 x 10"5
Realdenta NO NO
•
PD 4
WITHOUT PROTECTIVE CLOTH I HU HITU PROT8CTIVB CLOTHING
D»rioali/ Respiratory Dorval-i/ Respiratory-'


N/A N/A 1.3 0.012
0.23 H/A N/A

3 0.004 0.6 0.004
0.04 N/A N/A


0.4 ' 0.001 0.08 0.001
M/A N/A . 11 0.3^



7 X ID'* H/A N/A

0.2 N/A N/A
0.1 H/A N/A

0.3 0.2 0.06 0.2
0.02 H/A N/A
1.  formal exposure ••tlnat* la not nultlplled by akin absorption (actor.  T!il» is factored Into  risk estimates by Toxicology Branch.



                                                                               43

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   3.  Dietary  Exposure  to Lindane

More detailed information  on the Agency's  assessment of dietary risks from
lindane may be  found  in  a  document  prepared by  EPA's Environmental Fate
Branch (EPA, 198Ib).


      1.  The Agency's PD  2/3 Calculations

The Agency, in  calculating an estimate of  the dietary exposure of the general
population to lindane, used data showing average  lindane residues for 12
composite food  group  categories from the FDA market basket  (Total Diet
Composites) survey  during  the period from  1972  to 1975 (EPA, 1978).  From this
average, the daily  intake  of lindane in mg/1.94 kg diet for each composite
category was calculated, then totaled to get the  average daily exposure for all
12 food categories. This daily intake average was estimated to be
0.00266 mg/1.94 kg  diet/day, which  equals  0.038 ugAg bw/day for a 70 kg
adult.


      2.  Comment on  the Agency's Calculation of  Dietary Exposura

The Centre International d1Etudes du Lindane (rebuttal #94), represented by C.
Edwards, agreed that  the use of the market basket survey data was appropriate,
but that more recent  available market basket data should have been used. Also,
Edwards disagreed with the way certain FDA numbers were evaluated by EPA,
primarily that  trace  values were assigned  a value of 0.004 parts per million
(ppm) , when analytical techniques quantified residues considerably less than
0.004 ppm.

Imported dairy  products, according  to Edwards,  contained the largest proportion
of total lindane residues  up to 1975. In more recent years, however, sugar and
its adjuncts have had larger residues, with residues in meat and poultry
remaining fairly constant.  Edwards  suggested that contamination of food storage
bins was a likely source of lindane residues.

     NPDC (1983) disagrees with with the Agency's estimate of dietary
exposure with respect to the use of the 1976-1980 FDA data and the assign-
ment of a zero  value  to  trace residues.  The Agency agrees that the
complete data base  f ran  the FDA Market Basket Survey should be used in
estimating dietary  exposure to lindane.  The Agency has amended its PD
2/3 estimate to reflect  the entire  data base.   However, the Agency disagrees
on the issue of trace residues.  These points are addressed in B. 3. below.

      3.  The Agency's PD  4 Response

The Agency agrees that the -most current FDA market basket data (Total
Diet Composites) as well as historical data should be used to evaluate
lindane residues in the  diet of the general population. Data from 1964-1980
may be found in Table 5. With the exception of  1974, the residues of
lindane in the  diet in recent years (FY 1973 to FY 1980) have remained
relatively constant,  using FDA's methods of data  evaluation.  However,
the Agency has  new  used  the entire  data base as well as the most recent
(1976-1980) data to arrive at a range of exposure estimates.


                                     44

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                                                                 TAULB  4|


                                                        DAlLt BXPOSURB  TO LIllUAlIB


ABOVE SHOULDER SPRAYS
AIR BLAST Ol
POWER HAND GUM
ORNAMENTALS
(commercial)
AVOCADOS
PECANS
LIVESTOCK
ABOVE-SHOULDER SPRAYS
BACKPACK or
HAND PHESSURB
ORANMEIITALS
(homeowner e)
rORESTHY
CHRISTMAS TREES
(foliar)
CBAHI. SPACB TREATMENTS
STRUCTURES
Applicators
Residents
EXPOSURB WITHOUT PROTECTIVE CLOTHlNGl
log/kg bw/day)
DAYS BXPOSBD/YU DERMAL RESPIRATORY
4 H/A!/ H/A
2 2.3 4.6 x 1(TJ
1 2:3 4.6 x 10"1
1 H/A H/A
1 5.1 x 10~2 3 x 10"*
30-' H/A H/A
1 H/A H/A
5 H/A H/A
30/yr^ H^ 6.9 x 10~*
(once every 10 yr)
EXPOSURB WITH PROTECTIVE CLOTHlNGl
< ing/ kg bw/day)
DERMAL RESPIRATORY.!/
O.J7 8.6 x 10-«
0.46 4.6 x 10-3
0.46 4.6 x 10~3
0.11 1.5 x 10-*
1 x 10"2 3 x 10"*
2.7 x 10"2 1.3 x 10"*
7.8 x 10"2 2.3 x lO"3
1.5 x 10'3 7.7 x 10-*
H/A H/A
I-  »/.'. is uded for Not Applicable.  Calculations were »ada for 'Ho Protective Clothing" only in cases where none  is worn or there  is
    doubt about whether or not it is worn.  Simllary, calculations were not mads for protective clothing if the  situation does not  apply.

i.  :: ic- used (or Negligible Exposure.

3.  Subchronlc exposure based on 5 rag/kg/day NOEL (See VII., C.).

4.  Chronic exposure based on 1.25 mg/kcj/day NOEL (See VII., C.).

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   TAULB /• (Continued)




DMLK.KXPUaURE TO LdlDAHB

BXPOSUIIB WITHOUT PROTCCTIVB CLOTHINGS BXPOfiURB WITH PROTECTIVB CWlttlHQl
(»g/k
-------
                                                        TAULB 4  (Continued)




                                                     DA I Li EXPOSURE  TO l.Itlt...

EXPOSURE WITHOUT PIIOTECTI VB CI-OTIIINGl EXPOSURE WITH PROTECTIVE CLOTIIIHUl
•{ng/kg bw/day) (ug/kg bw/day)
DAYS BXPOSBD/YR DKHHAL RESPIRATORY DBRHAL RESPIRATORY
DIPS
UARDUOOD LOGS 20l4/ N/A H/A H 1.1 I 10' 3
k LUMBER
DOG DIPS
Veterinarian* 36?/ 6.1 « 11TJ H 1.] I 10"1 H
Post-tceatnent } H 8.* 1 10~* H/A N/A
Enposut* to ownoc*
DOG SUAHPOOS
Applicators 1 0.16 H 3xlO~2 negligible
Post-treatment 3 H 8.6 * 10"* N/A N/A
Exposure
ENCLOSED AREA SPRAYS
HOTII SPRAYS
Applicators
Employeeo
FUMIGATIOU DEVICES
UHINIIABITED BUILDING
26-^ 1.6 x NT1 l.J x 10'3 3.6 k 10~4 1.3 X lO'3
3/ .
78^ N 8 X 10~5 N/A . H/A
40 N 1.8 X 10~J N/A N/A
12?/ 6.2 X KT* 2.9 I ID'5 l.J X 10~* 2.» X KT5
I STORAGE DIN SPRAYS

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                                    TABLE  5

              AVERAGE DAILY  INTAKES OF  LINDANE  IN FDA TOTAL
                  DIET COMPOSITES  FROM  FY  1964  - FY 1980

  YEARS            RESIDUE INTAKE  (uq/k.q bw/day)        SOURCE OF DATA

1964-1969                 0.0500  (total)               EPA Position Document 1
1973                      0.0032                       DHEW Total Diet Studies
1974                      0.0034
1975                      0.0031
1976                      0.0025                       FDA Total Diet Composites
1977                      0,0039
1978                      0.0024
1979                      0.0038
1980                      0.0028
Quantitative residues, at  the  limit of detection, are subject to a high degree
of unreliability.  Therefore,  consistant with  FDA's analyses, the Agency did
not assign a numerical value to  trace findings.  In addition, assigning the
trace findings a value of  .004 ppm would not substantially alter the exposure
estimates shown below.

EPA agrees that imported dairy products contained the largest proportion of
lindane residues up to 1975, but that in more  recent years sugars and adjuncts
have had the largest proportion  of residues. Residues in meat and poultry have
remained fairly constant.  EPA  agrees that lindane use in empty storage bins
could be a source of these lindane residues; however, the residues are not
sufficiently large to be of concern.*

Using the FDA market basket surveys  (Total Diet Composites) for the more recent
period of FY 1976 - FY 1980, the average dietary intake is estimated to be
0.2141 ug/2.92 kg diet/day, which equals 0.0031 ugAg bw/day for a 70 kg adult.
This is a ten-fold reduction from the estimate used in PD 2/3.  Using the entire
FDA data base (1964-1980), the exposure is estimated to be 1.09 ug/day or 0.016
ug/kg/day.  This is a twofold  reduction from the estimate in PD 2/3.
                                48
   * The Agency will  reassess  the  adequacy of  lindane tolerances when
     it develops  the  registration  standard for lindane.

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V.  BENEFITS
     49

-------
The lindane PD 2/3 was based on a benefit analysis completed in June of 1978
(EPA 1978) That analysis expressed economic impacts in 1975-76 dollars.
Although it was not updated in FO 4 except for a few uses, the Agency assumes
in its PD 4 risk-benefit analysis that the economic estimates are understated.
That is, the nominal dollar measure of impacts is larger (due to inflation) for
uses which have been stable or expanding.

A complete use-by-use summary of EPA's PD 2/3 benefits analysis, discussion of
the comments received regarding benefits, and EPA's PD 4 final position on the
benefits of lindane are contained in the  Summary and Analysis of Benefits-
Related PD 2/3 Comnents (EPA, 1982c.) The following discussion provides a
synopsis of that analysis and its conclusions.

The Agency received 141 ccranents in response to the PD 2/3. The majority of
these addressed the high benefits and lack of alternatives for several key
uses. Almost none of these comments provided new information with which to
quantify the benefits, or new information about the existence of alternatives,
but the Agency considers that the large number of comments may provide
qualitative evidence of lindane1s benefits. Many of the points made in the
public comments were also raised in QSDA's comments to the Agency (see
Appendix I).

On a percentage basis, several uses accounted for the vast majority of the
comments received:

   Structural uses: Approximately 40% of the comments received addressed
   the structural use of lindane.  Most cited the lack of acceptable
   alternatives for controlling powder post beetles, especially since
   chlordane, a substitute for lindane, was cancelled effective March 6,
   1978.  Fumigant alternatives are generally considered unsatisfactory due
   to application problems and extremely high expense.  For these reasons,
   EPA concludes that the benefits of lindane are high for structural uses.

   Seed treatment: Approximately 25% of the comments received addressed
   seed treatment uses of lindane.  Again, most cited the lack of acceptable
   alternatives, and the usefulness of lindane as a control material.  In spite
   of the large number of comments received, there was no substantive
   information to suggest that previous estimates of the benefits of this use
   were wrong, or that the benefits could be quantified.  Most of the comments
   supported the Agency's PD 2/3 conclusion that cancellation of the use on
   small grains, lentils, and dry peas might cause major regional impacts at
   the user and market levels, but stated that these benefits had not been
   given adequate weight in the risk-benefit analysis.  Since alternative
   treatments are available for the corn use, benefits are lower for this
   particular seed treatment use.

   Ornamentals, forestry, and Christmas trees; Approximately 20% of the
   comments received addressed these three uses, all of which use lindane
   for control of wood borers.  Lack of alternatives was frequently cited; other
   pesticides are registered for borer control but lindane is the only
   pesticide registered to control all borers on all woody ornamentals.
   Although alternatives are registered for control of bark beetles (cultural
   management, oxyc!ernetonmethy1,  endosulfan, dicrotophos, and chlorpyrifos),
   commentors clai.ni that these are too expensive, ineffective, or relatively


                             1  .     50

-------
   more toxic than lindane. Also, there are claims that lindane is the only
   pesticide which is effective once trees are already infested, but there is
   conflicting evidence on this point. The Agency concludes that cancellation
   could have major impacts on the woody ornamental industry; small, privately-
   owned, Southern forest areas; and Southern Christmas tree farms. Impacts on
   the florist and foliage industries, and cool-climate forest areas and
   Christmas tree farms, would probably be significant but less severe.

   Animal uses; Approximately 15% of the comments received addressed
   uses on livestock and pets. Commentors claimed that restricting availability
   to pest-control operators and veterinarians would cause inconvenience,
   especially since toxaphene is the only equally effective alternative for
   controlling mites.   None of the the comments suggested revision of the PD
   2/3 benefit analysis, however, which projected minor impacts unless mites
   became an endemic problem.

   Hardwood logs and lumber: Approximately 8% of the comments received
   addressed the hardwood logs and lumber use.  Most attested to the usefulness
   and necessity of lindane for protection of hardwood lumber.   CIEL (rebuttal
   #94) estimated! that due to increased lumber prices, annual impacts were
   approximately $100 million larger than EPA had estimated.  Another ccmtnentor
   stated that EPA had overlooked the availability of endosulfan as an
   alternative for this use (comment #134.)  EPA acknowledges that the price
   of lumber and therefore the value of the hardwood use of lindane has
   increased, and that endosulfan is registered for this use.  Although the
   dollar benefits could not be quantified, lindane is clearly a valuable
   control material for protection of hardwood logs and lumber.

   Minor uses: EPA received several comments pointing out the considerable
   benefits of lindane use for minor uses which were not addressed in PD 2/3,
   including use for preserving historic artifacts, and use on sugar cane
   (the latter is currently allowed only as an emergency use).   Although
   these are minor uses, EPA acknowledges that cancellation of lindane would
   have major impacts on efforts to protect historical artifacts,  and on the
   sugar cane industry.  EPA agrees that there are probably substantial
   benefits from these two uses of lindane, and perhaps frcm other uses  '
   which can not be analyzed separately.  The magnitude of those benefits
   can not be quantified.

(Note: the percentages of contnents received for the use categories above add
to more than 100% because some comments addressed more than one use.)

A summary of the results of the PD 4 benefits analysis are as follows:

   High benefit uses (no alternatives; significant impacts if cancelled):

   - woody ornamentals, including Christmas trees (no alternatives to control
     wood borers)
   - forestry (registered alternatives significantly more expensive and perhaps
     inefficacious against some pests)
   - seed treatment (possibly major regional impacts)
   - structures (alternatives significantly more expensive, inconvenient,
     and toxic)
   - avocados (moderate impacts nationwide, but severe impacts  in Florida)


                           '•  .     51

-------
- historic preservation (no alternatives against powder post beetles)
- hardwood logs and lumber (clearly valuable as a control method,  although
  endosulfan is available)
- dog dips (many alternatives for most uses, but no equally effective
  alternative for treating scabies)


Moderate benefit uses (alternatives may be unavailable but impact  if lindane
were unavailable is minor, or alternatives are significantly more  expensive,
or alternatives are less efficacious)

- floral and foliage ornamentals (no alternatives for certain pests but
  cancellation would not cause major economic'impacts)
- livestock dips (alternatives available but only toxaphene is equally effective
  against scabies);
- sugar cane (currently in use under emergency exemption provisions)
- pineapples (alternatives more expensive and less effective)

Low benefit uses (alternatives exist,  or unavailability of lindane would
result in only minor losses)

- cucurbits (numerous satisfactory alternatives)
- pecans (alternatives slightly more expensive)
- all household products except dog dips (numerous satisfactory alternatives)
- enclosed area sprays (numerous satisfactory alternatives)
                                 52

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VI.  SUMMARY of KEY RISK-BENEFIT CONSIDERATIONS
                        53

-------
This chapter summarizes  SPA's  conclusions  about  the risks and benefits of
iindane.


   A. Oncogenicity  : Key Points

Several  independent laboratory studies  have  been used to evaluate the oncogenic
potential of lindane.  The  evidence  that lindane is carcinogenic in mice is
based on two lifetime  studies, those by Thorpe and Walker and by NCI.  Two
subchronic studies  by  Goto  et  al.  and Hanada et  al. provide supportive evidence
of oncogenicity.  Primary responses  were seen in the liver, an organ with
high background  tumor  rates in the strains tested, but metastases to other
organs were observed in  some cases.

The scientific community is currently debating whether or not increased
mouse liver tumors  are predictive  of human carcinogenicity, especially in
the absence of positive  mutagenicity data, or induction of primary tumors at
other sites.  One position  is  that such tumors provide suggestive evidence
that the chemical may  act by promoting  carcinogenesis rather than acting as
a "complete" carcinogen.  Questions  have been raised about the appropriateness
of using linear  risk extrapolation models  (such  as the linear multistage) for
lindane where mouse liver tumors have been the primary carcinogenic response.
                          !
As indicated above,  information regarding  a chemical's mutagenic potential
may provide valuable information for evaluating  the mechanism by which that
chemical may cause  cancer.   However,  mutagenicity information on lindane is
at this time inconclusive.  More extensive  short-term testing for genotoxicity
could provide useful information on  the mechanistic questions associated
with lindane1s oncogenic activity.

It is prudent for EPA  to presume that any  agent  which causes tumors in animals
has potential to cause carcinogenic  effects  in humans.  For lindane the
Agency has used  quantitative risk  estimates derived from the available mouse
data, and has extrapolated  risks using  the linear, multistage model (See
Table 6).

The risk numbers in PD 4  and PD 2/3  differ as a  result of changes in the
risk extrapolation  procedure (i.e.,  the use of a 95% upper limit estimate),
an interspecies  scaling  factor, and  in  exposure  estimates.  While this change
in extrapolation procedure  and inclusions  of the scaling factor caused an
increase in the  potency  estimate,  the exposure estimates in most cases were
decreased.  Differences  in  the interpretations of the significance of those
numbers are due  to  the fact that the Agency recognizes the uncertainties
surrounding these estimates, as described  above, and has developed its
regulatory conclusions accordingly.


   B.  Fetotoxicity/Reproductive Effects : Key Points

Lindane causes fetal effects in test animals only at or above doses which also
cause general toxic effects in the mother. Therefore, protecting mothers from
                                     54

-------
toxic effects will simultaneously protect fetuses frcra possible adverse effects.
The NOEL for general toxic effects (anorexia and CMS effects) is 5 mg/kg/day.

Since the toxicologic effects observed at 5 mg/kg/day and below are reversible,
(See Section III.A.2.6) a margin of safety somewhat less than 100 might be
considered adequate to protect most exposed populations fron the CMS effects.
However, since fetal effects occur above 10 mg/kg/day, EPA concludes that a
margin of safety of more than 100 for these effects is attained for all uses
and specific warnings or restrictions are not necessary.

   C. Acute Hazards to Hunans and Domestic Animals

Information available from reproductive an chronic toxicology studies, specific
neurological studies, and clinical investigations suggest that the NOEL for
acute CNS effects is around 5 mg/kg/day.  Most of the animal studies that
investigate lindane's neurological effects are more specific than conventional
screening studies, and they suggest lower no-effect levels for specific nerve
functions in comparison to the more generalized toxicity tests.
                                                        i
Based on these considerations, the Agency believes that the 5 mg/kg/day NOEL
is an adequate no-effect level with respect to acute CMS effects.  It is
unlikely that lindane causes permanent neurological damage at the levels and
conditions under which humans will be exposed.

   D.  Susceotibilitv of Children
In view of the results reported by Hanig et al. (1976), and the episodes
involving lindane and children, and additional conraents and data , the Agency
is still concerned that children may be more susceptible to the toxic effects
of lindane.  As stated previously by the Agency, there is still insufficient
data on which to base separate Margin Of Safety calculations for children.
                                      55

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   S.  Possible Association Between Lindane and Bleed  Dyscrasias;

Several case studies,  cited by the Agency in PD 1,  indicated  that blood
cyscrasias might  be  associated with exposure to lindane.  However, these cases
do not satisfy epidemiolcgic criteria for establishing a  cause-effect
relationship between lindane exposure and blood dyscrasias.

A recent epidemiology  study (Morgan 1980)  in Iowa showed  no correlation between
lindane blood levels and the occurrence of adverse  hematologic effects.
However, because  blood dyscrasias  are extremely rare,  the study size was not
large enough to provide statistically significant results.  In conclusion,
available epidemiological data on  lindane do not establish a  cause-effect
relationship between lindane and blood dyscrasias.

   F.  Acute Tcxicity  to Aquatic Wildlife

Lindane is known  to  be quite toxic to aquatic wildlife, but is not presently
registered for direct  aquatic application.  Therefore,  the chief concern is to  *
avoid  application,  handling,  or disposal practices which cculd result in
significant drift or runoff into water,  such as aerial application or improper
disposal.

   G.  Key Points in the Exposure  Analysis

The exposure estimates used in the original PD 2/3  analysis were purposefully
conservative, since  they were based on highly uncertain information and EFA
prefers in such cases  to err on the side of safety.  Since the proposed
decision was published,  EPA has been able to improve its  estimates significantly.
Seme of the revisions  in PD 4  are  based on new information, while others
are based on the  use of better surrogate data.   Details of all the changes
in the exposure analysis and the reasons for them may  be  found in Appendix
III.  Table 3 compares the exposure calculations in PD 2/3 with those in
PD 4.

Dietary exposures are  estimated to be low.   The estimates are based on actual
residue monitoring data.   Lindane  is one of a comparatively few compounds for
which considerable historic and current monitoring  data exist.  In light of
1) the current use patterns of lindane,  2)  of current  label application re-
strictions and directions,  and 3)  of actual monitoring data,  the Agency
believes dietary  exposures are low.

In ^general, dermal exposure is by  far the most significant route of exposure
to humans.  Certain  application methods  involve significantly more exposure
(and therefore risk)  than others.   Overhead spraying,  fumigation, and dipping
tend to have the'*  highest exposures associated with  them.   Mixer/loaders are
also known to be  exposed to high active  ingredient  concentrations, but their
exposure levels were not separately calculated.   Total exposure varies according
to duration of exposure and not just application method.
                                  '   56

-------
   H.  Key Points in the Benefits Analysis

The considerable benefits of lindane's use are given more weight in the
PD 4 decision than the PD 2/3 proposal, as was suggested in the many
compelling comments which the Agency received from the numerous parties.
The decision proposed in 1980 was criticized by the U.S.  Department of
Agriculture, the Scientific Advisory panel, and the public, for not adequately
considering lindane's benefits.  The Agency agrees that the benefits
were not adequately considered in its original assessment, and has revised
the risk/benefit analysis accordingly.

The highest benefit uses are those for which the use is economically
important and there are no alternatives. These include uses against
wireworms (seed treatment), all uses against wood borers (forestry,
woody ornamentals, Christmas trees,  hardwoods, structures, and historic
preservation), treatment of scabies  (livestock and dog dips), and treatment
of mirids on avocados.                                                      I

All the other agricultural uses have moderate benefits except for pecans
and cucurbits, for which numerous alternative pest control methods are
available.

Low benefit uses include pecans, cucurbits, enclosed area sprays and
all household uses except dog dips.
                                    57

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VII.  RISK-BENEFIT ANALYSES
              58

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   A.  General notes

The process of balancing risks and benefits is difficult and necessarily
subjective.  EPA is required by FIFRA to insure that pesticides do not present
"unreasonable risk".  A finding of "unreasonable risk" means that the risks
outweigh the benefits, and that available risk reduction measures, short of
cancellation, cannot lower these risks sufficiently to insure that the
benefits outweigh them.  In most cases, risk reduction measures short of
cancellation are sufficient to bring the risks and benefits to a reasonable
balance, and they are required for that purpose.

EPA's final decision on the pesticidal uses of lindane, presented in this
chapter, gives more consideration to the benefits and the regulatory options
short of cancellation than the PD 2/3.  It is also based on significantly
better information than the decision proposed in 1980.  The final decision
has been carefully designed to insure that immediate but minimally burdensome
steps will be taken to protect any populations which may be at risk, to
preserve the benefits of lindane1s use, and to insure that uncertainties
surrounding certain of the risks will be reduced within a reasonable time
frame.

In this chapter, risk-benefit considerations for six use groups are presented.
The groups were categorized by application methodology, which correlates well
with exposure and also risk.

The phrases "without protective clothing" and "with protective clothing"
occur repeatedly in the discussions regarding exposure.  "No protective
clothing" means that EPA assumes that the applicator's head is uncovered,
and that a v-necked t-shirt and pants are worn.  "Protective clothing"
varies for each use; the reader may refer to the Exposure Analysis Narrative
(Appendix III) for use-by-use descriptions, unless otherwise indicated.


   B.  Interpreting the quantitative cancer estimates

The risk estimates discussed below must be interpreted according to the
perspectives discussed in earlier parts of this document.  As was noted
earlier, the evidence that lindane is carcinogenic in mice is based on two
lifetime studies, Thorpe and Walker and the NCI study.  Both studies show
that oral administration of lindane causes hepatic tumors.  However, in the
best carcinogenicity study, Thorpe and Walker, only a single dose of lindane
was tested.  Two subchronic studies in mice, Goto et al.  and Hanada et al.,
provide supportive evidence consistent with that found in the two lifetime
studies.  In addition, 2,4,6 trichlorophenol, a metabolite of lindane, is
carcinogenic in rats and mice.  Mutagenicity testing in lindane is indeter-
minate and does not allow the Agency to confirm or refute the genotoxicity
of this chemical.  Based on the information above, the linearized, multi-stage
model was used to provide an upper limit risk estimate of potential human
risk.

Another uncertainty exists due to the fact that the cancer risk
                                     59

-------
estimates are based on an assumption of  lifetime exposure to lindane.  Except
in cases where people are exposed  for a  lifetime (the Agency assumes 35 years
for applicator exposure and 70  years for household product exposures), these
estimates tend to overstate the actual risks.

In spite of these uncertainties, EPA presumes that a chemical which has
the ability to cause tumors in  animals has  the potential to cause carcinogenic
effects in humans.  The Agency  also assumes that seme people may be exposed
to the chemical over their entire  lifetimes.  Both of these assumptions are
based on the desire to make estimates which are expected to err in favor of
protecting human health.  However, the uncertainties are taken into account
in a qualitative sense in the risk-benefit analysis.

These facts mean that the quantitative cancer risk estimates discussed below
are subject to significant uncertainty.  Thus, although these numbers are
based on the best information available  at  this time, they may be subject to
a margin of error of at least one  order  of magnitude in either direction.
It is expected that the actual  risks are lower than the estimates obtained
using linear models.  The Agency therefore uses these estimates primarily
for determining relative risk levels from one use group to another, and to
show the upper bound of potential  risk.

   C.  Margin of Safety Estimates

The considerations discussed in Chapter  II  lead the Agency to conclude
that a no-observed effect level (NOEL) of 5 mg/kg/day is appropriate for
general toxicity while a NOEL of 10 mg/kg/day is appropriate for fetotoxic
effects.

Another of lindane's possible effects, which may correspond with the general
toxicological effects, is increased liver weight.  The EPA did not (critically)
review in detail the many chronic  and sub-chronic studies which have shown
liver weight increases in test  animals because this effect was not related
to an RPAR criterion discussed  on  PD 2/3.  However, a general review of the
literature shows that 1.25 mg/kg/day is  the NOEL with respect to liver weight
increases from chronic exposure (Burnam, 1982).

Margins of safety (MOS) for general toxicity, fetal effects in the presence
of general toxicity, and chronic liver toxicity (enlargement) are calculated
by dividing the NOEL by exposure,  expressed as mg/kg/day.  Table 2 lists
MDS values.  For fetotoxicity,  these MOS values can be doubled for most uses
based on a 5 rng/kg NOEL.  The hardwood logs and lumber, flea collars, and
shelf paper uses involve chronic exposures and a NOEL of 1.25 mg/kg was used
to calculate the MOS for these  three uses.
                                     60

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   DO  Risk/Benefit SuKaaary Tables

Table 6 sissaarizes all the information used in the risk-benefit analysis:  the
quantitative risk calculations, qualitative benefits calculations, and expose.
populations ("cohort at risk").  Table 7 sunraarizes the same information,  but
for PD 2/31 it may be used to compare the risk and benefit conclusions of
    PD 2/3 with the PD 4.
                                     61

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                                                              TABLE 6

                                    USE BY USB SUMMARY Of ESTIMATED LINDANB RISKS  AND BENEFITS
        USB
            COHORT            MARGIN OP SAPBTvl/
BENEFIT       AT       (Gen'l Tox. and Fetal Effects)
             RISK   w/out prot. cloth, with prot. cloth.
                                                                                             CANCER
                                                                                 w/out prot. cloth.
                                                                        Protective
                                                                       clothing worn
                                                      with prot. cloth, routinely?
ABOVE SHOULDER SPRAYS
  AIR BLAST PC
  POWER BAND GUN

     ORNAMENTALS
     (commercial)

     AVOCADOS

     PECANS

     LIVESTOCK
  high
               600
high           ?

low        1,200

medium   248,000
                             22

                             21

                           N/A
                      280


                       99

                       99

                      448
                N/A
                                                                      ,-4
              6.9 x 10

              3.5 x 10'4

                N/A
                        l.l X 10"*
                                           ,-4
                        1.5 x 10

                        7.4 X 10"5
                        1.7 x 10
                                ,-5
                                   yes


                                   no

                                   no

                                   yea
ABOVE SHOULDER SPRAYS
  BACKPACK or
  HAND PRESSURE

     ORNAMENTALS        high      75,000
     (homeowners)

     FORESTRY           high       1,000

     CHRISTMAS TREES    high      10,000
       (foliar)
                            926


                           N/A

                           N/A
                     3846


                     1767

                      500
            8.1 X 10'6


                N/A

                H/A
                        1.9 x 10"
                        1.2 X 10
                                r«
                        1.2 X 10
                                ,-5
                                   no


                                   yes

                                   yes
CRAWL SPACE TREATMENTS

     STRUCTURES

       Applicators      high

       Residents        high
             8,000

                 ?
N/A

7246
5435

 N/A
    N/A

5.9 X 10
,-6
7.4 X 10'

  N/A
                                                                                                     yes

                                                                                                     no
1.  Calculated using expected daily exposures.
2.  Calculated using expected annual exposures.
3.  Not Applicable.  Calculations were made for 'No Protective Clothing* only in cases whet*  none is
    worn or there is doubt about whether or not it is worn.  Similarly, calculations were not *ade for
    protective clothing if the situation does not apply.

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                                                        TABLE 6 (Continued)

                                    USB BY USE SUMMARY OP ESTIMATED LINDANB RISKS  AND BENEFITS
                                  COHORT            MARGIN OF SAFETY-i/                       CANCER RISK-?/               Protective
        USB            BENEFIT        AT        (Gen'l Tox.  and Fetal Effects)                            .                 clothing worn
             •                     RISK    w/out prot.  cloth, with prot. cloth.   w/out prot. cloth.    with  prot.  cloth, routinely?
DIPS
     HARDWOOD LOGS &
       LUMBER
high
     DOG DIPS

       Applicators

         Veterinarians  medium
D«840         N/A
R-2400-/
              130,000     B197
                                                                       962
                                                               N/A
       Post-treatment
       Exposure to
       owners

     DOG SHAMPOOS
mediun     15,000,000    58140
       Applicators      low
       Post-treatment
       Exposure
low
                                                   312
                         58140
                                   71667
                                     N/A
                                                                      1562
                                     N/A
2.4 x ID"
                                                             4.2 x 10
                                                                     -7
                                                             2.2 x 10
                                                                                             -5
4.2 x 10
                                                                     -7
                                                                       3.6 x 10
                                                                                                                  ,-4
4.2 x 10



  N/A



4.5 x 10


  N/A
                                                                                          1-6
                                                                                                                  -6
                                         yes
                                                                                                     no
ENCLOSED AREA SPRAYS

     MOTH SPRAYS

       Applicators      low

       Employees        low

     FUMIGATION
       DEVICES          low

     UNINHABITED
     BUILDING & STORAGE
     BIN SPRAYS         low
                          3378

                         55556


                          2631



                         54945
                                   37425

                                     N/A


                                     N/A



                                 121,957
5.6 x 10~5

3 x 10"5


1.4 x 10~4



1.5 x 1Q"6
5 x 10~5

  N/A


  N/A



6.4 x ID" 7
no

no


no



no
4.  *D* represents dermal exposure.
5.  *R* represents respiratory exposure.

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                   TABLE 6 (Continued)
USB BY USB SUMMARY OF ESTIMATED LINDAHB RISKS AMD BENEFITS
*
•
USB BENEFIT


DUSTS
SEED TREATMENT
Applicators high
Seed Sowing high
DOG DUSTS
Applicators low
Post-treatment low
Exposure
BELOW SHOULDER SPRAYS
CUCURBITS low
CHRISTMAS TREES high
(stump/slash)
PREPLANT SOIL APPLICATIONS
PINEAPPLES nediUB
HOUSEHOLD PRODUCTS (OTHER)
FLEA COLLARS low
SHELF PAPER . low
COHORT MARGIN OF SAFETY^ CANCER RISK^/ Protective
" AT (Gen'l Tox. and Fetal Effects) clothing worn
RISK w/out prot. cloth, with prot. cloth. w/out prot. cloth. with prot. cloth, routinely?

.

130,000 N/A 5000 N/A 3 I 10~6 yes
130,000 2941 N/A 4.9 1 10~6 N/A no

? 2763 11628 6.4 I 10~6 1.4 K 10~6 no
? 58140 N/A 4.2 Xl0"7 N/A no
-
1
950 28736 131579 . 8.7 « 10"7 1.9 x W7 no
10,000 N/A 256 N/A 3 x 10~5 yes


1600 1000000 N/A 1.5 « 10~JO N/A no

? 145^49 N/A 4.2 • 10"' N/A Gto
11,000,000 725000 N/A 2.1 a 10~* N/A no
HOUSEHOLD SPRAYS



  Applicators      low




  Residents        low
 1370




53556
                                 1320
 4.9 8 10~e




.-4,2;* I0~7
.4.4.8
                                                                           "6
                                                                                      no
                                         64

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                                        USE BY USE SUMMARY OF PI) 2/3 ESTIMATE!)  LINDANE RISKS AND BENEFITS*
USE BENEFIT COHORT MARGIN OF SAFETY1 MARGIN OF SAFETY
AT RISK General Acute Toxiclty Fetotoxicity
w/out prot. cloth, with prot. cloth, w/out prot. cloth, with prot. cloth.
LIFETIME CANCER.
PIWHAUILITY
w/out prot. cloth w/prot. cloUi.

ABOVE SHOULDER SPRAYS
AIR BLAST or
POWER HAND GUN
ORNAMENTALS Medium 30-1200 6-16 42-125 12-31 83-250
(oamnerlcala)
AVOCAOOS Medium MO3 4 15 7 31
PECANS lot 1200 4 15 7 31
LIVESTOCK Low 248,000 >100 >100 >100 MOO
ABOVE SHOULDER SPRAYS
BACK PACK or
HAND PRESSURE .
i
ORNAMENTALS Medium 75,000 47 >100 94 >100
(haneowners) ,
FORESTRY Low 1,000 IB 21 36 42
CHRISTMAS TREES High 10,000** 2-37 9-70 4-75 16-139
(foliar)
CRAWL SPACE TREATMENTS
STRUCTURES Minor if
PCP Available
Applicators 500- 3 18 5 37
1000
Residents ' 10,000 3 N/A4 >100 N/A
7x10 \ - 4xlo~I ~ '
3xlO~J 9xlO~b
6xlO~4 2xlO~6
3xl04 8xHf5
5xlO~6 Ixio"6
2xlO~5 6x!0"6
2xlO~3 6xlO"4
4x10";* - 2x10"^
7x10 2x10
9xlO~3 3xlO"3
5xlO~4 N/A
*  Risk estimates apply to applicators, unless otherwise indicated.
1. Calculated using expected dally exposures.
2. Calculated uslnQ expected annual exposures.
3. NO <• Not Determined
4.W/A  -?:Not Applicable
                                                                               65

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''*" f 'T •••. . 1 1 -. 1
USE UY USE SOMMARY«OF ESTIMATED PI) 2/3 I.INOAHE RISKS AND BENEFITS*
USE WNEFIT
POSTS
SEED TREA'IMEWr Possibly
major except
App licatora corn
Seed Sowing
DOG DJSfS low
Appl Icators
Post- treatment
Ex(>osurc
BEIJOW SHOULDER SPRAYS
CUCURBITS low
CHRISTMAS TREES
(stunp/slaeh) high
PREPIANF SOIL APPLICATIONS
PINEAPPLES low
HOUSEHOLD PRODUCTS (OTHER)
FI£A COLLARS low
SHELF PAPER low
HOUSEHOLD SPRAYS low
Applicators
Residents
COHORT MARGIN OP SAFETY1 MARGIN OF SAFETY1
Kf RISK General Acute Toxlclty Fetotoxlcity
w/oiit prot. cloth. with prot. cloth, w/out prot. cloth, with prot. cloth.

130,000
14 >100 28 >100
ND ND , ND ND

N/A >1000 N/A >1000 N/A
ND >1000 N/A >1000 N/A

950 >1000 >1000 HOOO >1000

10,000 ND ND ND ND
1600 >1000 N/A >1000 N/A
NO >1000 N/A >1000 N/A
11,000,000 >1000 N/A >1000 N/A

ND >1000 N/A >1000 N/A
NU ND NL> «) ND
LIFETIME CANCER
PHGUAIUL1TY
w/otit prot. cloth w/prot. cloth.

OxlO~5 5xlO~6
ND ND

2xlO~5 N/A
2xlO~5 N/A

4xKf6 4xlO"7

ND ND
10~12 N/A
2xlO~4 N/A
4xlO"5 N/A

6xlO~U N/A
ND ND
66

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TAI>1£  1 (Continued)
USB UY USE SUMMARY OF ESTIMATED PI) 2. ^NDAHE RISKS AMU UENEFITS*
*
SB
IPS
: HARDWOODS
DOG DIPS
Veterinarians
! Dane Applicators
\ Post-treatment
Exposure
i DOG SHAMPOOS
! Appl icators
Post- treatment
1 Exposure
i
.•CLOSED AREA SPRAYS

rtmi SPRAYS
| Appl icators
1
i Biployees
fUMIGATION DEVICES
! UNINHABITED
' BUILDING i, STORAGE
DIN SPRAYS
BENEFIT COHORT MARGIN OF SAFETY MARGIN OF SAFETY
At Risk General Acute Toxiclty Fetoloxiclty
w/out prot. cloth, with prot. cloth, w/out prot. cloth, with prot. cloth,
— .

high 2400 11 42 22 83
low
130,000 >1000 >1000 >1000 >1000
ND >1000 H/A >1000 H/A
15,000,000 >1000 H/A >1000 H/A

low
ND >1000 H/A ; >1000 H/A
ND >1000 H/A .' >1000 H/A

probably
low

ND >|0()0 N/A >1000 H/A
IV >100 H/A >100 H/A
low ND >100 H/A >100 N/A
probably ND 68 H/A >100 N/A
low ,
LIFETIME CAJICfU
PIOIWIII.ITY
w/out prot. cloth w/prot. cloth.


3xlO"2

2xlO"7
ND
7xlO"6


4xlO""5
2xlO~6


~-
IxlO"6
IxlO"5
lxlO~3
2xlO-6


7x10 3

5xlO~8
M)
H/A


H/A
H/A



N/A
N/A
H/A
H/A
              67

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   £.   Risk-benefit analyses for seven key routes of exposure,  and use-by-use
        final determinations

      1.  Above-shoulder spray applications - air blast  or pcwer hand gun
          equipment

The uses which  fall into this category include comercial ornamentals,
avocados, pecans,  and  livestock. Applicators typically use power hand gun
equipment for use  on ornamentals and livestock.  Air blast equipment  is used in
avocado, pecan,  and other types of orchards. Air blast application results in
more exposure than pcwer hand gun equipment.

Exposure calculations  for these uses show exposure to applicators to be higher
than fron any other route of exposure to lindane.  Even assuming that protective
clothing is worn,  this high exposure generally results in low margins of
safety  (MDS) for toxic effects:  the estimated MDS for avocado and pecan
applicators is 99  and  for ornamental applicators is 280; however, livestock
applicators have an MDS of 448.  Upper-bound cancer risks range frcm
l.lxlO*"4 to 1.7xlO~5 even when protective clothing is worn.

The number of applicators for these uses is in the range of 1-2 thousand,
except  for the livestock use, which may involve 200-250  thousand.

The benefits of  all four air-blast and pressure hand gun uses are high in
the sense that cancellation would cause either large or  very geographically
concentrated eccnonic  losses.

Taking  all of these considerations into account,  the Agency has decided to take
the following actions  for each of these uses:


            Commercial Ornamentals;

The risks associated with this use are significant, as with all the air blast
uses.   Specifically, the potential cancer risk is  estimated to be l.lxlO"4
even if protective clothing is worn.   The MOS  with protective clothing is 280.

The benefits are high  for use on ornamentals,  since there are no alternatives
for controlling  all wood borers on all woody ornamentals.  Cancellation
would cause major  economic losses (approximately S20.6 million) to homeowners
and to  the woody ornamentals industry,  due to  borer damage.

Both the risks and the benefits of this use are  significant.  However,
EPA does not believe that cancellation is warranted,  since the benefits
of this use are  so high,  the number of applicators potentially at risk
(approximately 600)  is low, and stringent protective measures
                                      68

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(described below) can be used to insure that the benefits exceed the risks.

Protective clothing would not significantly increase costs associated with
this use, but would significantly reduce the risks. Therefore, the following
protective clothing will be required for applicators:  water resistant hat;
lightweight protective suit or coveralls; unlined, waterproof (i.e., natural
rubber, polyethylene, neoprene etc.) gloves; and unlined, lightweight boots.
Mixer-loaders will be required to wear goggles or face shield, waterproof
gloves and a waterproof apron.  (Risks for mixer-loaders were not calculated
separately from applicator risk, but it is known that their exposure is
80-90% higher per unit time.  Therefore, EPA believes this requirement is
appropriate.)

Since the margin of safety may be less than 100 if protective clothing
is not worn, it is important to advise persons who may be at particular risk of
the importance of using the clothing indicated. Therefore, EPA will classify
this use for restricted use only, thus insuring that this application method
could only be used by or under the direct supervision of trained applicators.
By preventing untrained or unsupervised applicators from applying lindane
with air blast or pressurej gun equipment, risks of unacceptably high exposure
due to carelessness would be significantly reduced.  This restriction will
not impose an undue burden since there are already many certified applicators,
and training and certification programs are readily available.

Registrants will also be required to update their product labels to meet
current standards. Labels must describe proper handling and disposal,
symptoms of poisoning, practical treatment in the event of poisoning, and
other warning statements appropriate, for the product's toxicity category
(See 40 CFR 152.10).


            Avocados:

Risks associated with the avocado use are also significant.  Even if
protective clothing (long pants, long-sleeved shirt, waterproof gloves,
shoes, hat) is worn, the cancer risk is estimated to be l.SxlO"4.
The MOS for the toxic effects is 99.  This margin of safety is
considered acceptable for the reversible "general" toxicity, and also affords
a sufficient MOS for fetotoxic effects (See C. Margin of Safety Estimates in
this Chapter).

There are no registered alternatives for control of mirids on avocados.
The benefits of this use are very high in Florida; cancellation there would
cause major economic losses (approximately 58.7 million in producer losses
due to downgrading and fruit loss).  However, the impact of cancellation
would be negligible outside of Florida - although avocados are grown in
other states, the target pests (mirids) are not currently a problem outside
of Florida.

The risk-benefit balance for this use is again a difficult one, since both
the risks and benefits are significant.  In EPA's judgment, cancellation
                                     69

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is not warranted since  less  stringent measures  could reduce the risk
levels, since  the  benefits are high (there are  no suitable alternatives for
control of mirids), and since cancellation would  have a major deleterious
impact on the  Florida avocado industry.

EPA extensively investigated various ways  to reduce the risks associated with
this use.  It  does not  appear feasible  to  alter the application equipment
(air blast), reduce the active ingredient  concentration, or apply lindane
less frequently.

In conclusion, although the  risks  cannot be eliminated, stringent protective
measures will  reduce them enough so that the benefits (which are high) will
exceed the risks.  Therefore,  SPA  will  retain lindane's use on avocados, but
will impose stringent protective measures.   These include:

0 Requiring the sarre protective work clothing for applicators and mixer/loaders as
  stipulated for commercial  ornamentals:
0 Restricting  the  use to certified applicators;
0 Requiring label  updates, to include proper handling and disposal, symptoms    •
  of poisoning, practical treatment in  the event  of poisoning, and other warning
  statements appropriate to  the product's  toxicity category.


            Pecans;

Risks associated with lindane  use  on pecans are similar to the risks described
above for avocados.  Even with protective  clothing,- the upper-limit cancer
risk is estimated  at 7.5xlO~5.   The MOS for general, liver, and fetal
toxicity i-s 99.

Economic losses if lindane were not available would total approximately $1.5
million annually,  due to a combination of  increased control costs and crop
losses.  There are alternatives for controlling pecan phylloxera, however,
these alternatives also have potential  risks associated with them and are
subject to the same high-exposure  application method as lindane.  Endosulfan,
lindane's major alternative,  is in a higher toxicity category than lindane
and is usually applied  twice as often. Also,  there are serious uncertainties
regarding its environmental  effects and its potential to cause kidney damage.
                                     70

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Other pesticides (malathion, oils) are registered for this use, tout  they
are not as effective and require more frequent application.

Approximately 1,200 applicators are estimated to be involved in the  pecan use.

Since cancelling this use might promote the use of a pesticide with  potentially
higher risks, since other alternatives are less effective, and since the
benefits exceed the risks if appropriate measures are taken, cancellation of
the registrations for pecan use is not warranted.

EPA explored many options other than cancellation.  Measures such as different
application equipment, lower concentrations, and fewer applications  are either
impractical, or would not significantly reduce the risk.  The only viable
option is to require protective clothing for applicators, which is reasonable
in this case since lindane is applied to pecans in early Spring.

Considering the above points, EPA will take the following steps to insure the
benefits of lindane's pecan use exceed the risks:

0 Classify lindane pecan products for restricted use;
0 Require the same protective clothing as with commercial ornanentals use.
0 Require label updates, including descriptions of proper handling and disposal,
  symptoms of poisoning, practical treatment in the event of poisoning, and
  other warnings appropriate for the product's toxicity category.


         Livestock

Lindane livestock uses may be divided into two primary application categories:
livestock dips and sprays.  Applicator exposure from the dips is insignificant
compared to exposure during spray operations.  Also, a pharmaceutical product,
which controls mites and ticks, is currently in the final stages of development.
If approved, this product could soon make lindane dips (but not sprays)
obsolete.  For these two reasons, we have considered livestock sprays separately
fron the dips for risk and regulatory analysis.

The following discussion applies only to livestock sprays. Other lindane
products for treating livestock will be regulated similarly to products which
share their exposure potential. For example, livestock dips.will be subject to
applicable requirements fron the dips category (see Chapt. VIII, D.), and topical
gels will be subject to requirements similar to other uses where the applicator
cones directly into contact with the material, such as lindane sharapocs, also
see Chapter VIII, D.
                            -  . 1 71

-------
Assuming that  long-sleeved shirts,  long pants, and waterproof gloves are worn,
the cancer  risk  associated with livestock sprays  is estimated to be 1.7x10"^.
The "OS for general  toxicity is 448.

The economic losses  if  lindane were not available for this use would be
moderate.   However,  one of lindane1 s most important uses  is for scabies
control.  Alternatives  exist for livestock use, but with  the exception of
toxaphene,  are less  effective (EPA  1982c).

The risks and  benefits  of  this use  are  both significant.  However, EPA believes
that if appropriate  measures tc reduce  the risks  are taken, the benefits
outweigh the risks and  cancellation is  not warranted.

EPA examined many options  for reducing  the risk without cancelling these
uses.  The  concentration of lindane would have to be reduced a great deal to
result in a significant improvement in  the risk estimates, and other application
methods are not  currently  feasible.   Hence,  none  of thse  options provides a
way to reduce  the exposure without  seriously compromising either efficacy or
practicality.                                                                    »

Considering the  combination of fairly high risks  and benefits from livestock
uses of lindane, EPA will  require all reasonable  restrictive actions short of
cancellation.  This  will insure that the benefits of this use exceed the
risks.  Measures which  will be required include:

0 Protective clothing requirements  for  applicators and mixer/loaders are the
  same as for  commercial ornamentals;
0 Restricted use classification (since  the Agency anticipates that persons
  trained in the risks  of  pesticide application are more  likely to read the
  labels and to  take the required precautions).

Registrants will also be required to update their product labels to meet
current standards. Labels  must describe proper handling and disposal, symptoms
of poisoning,  practical treatment in the event of poisoning, and other warning
statements  appropriate  for the product's toxicity category.


      2.  Above-shoulder sprays - backpack or hand-pressure equipment

The uses which fall  into this category  include forestry,  foliar treatment
of Christmas trees,  and hcneowner ornamentals.  Back-pack sprayers are used
for forestry and Christmas tree uses, while hand-pressure equipment is
typically used for non-professional application to ornamentals.

Exposure levels  associated with this  use category are higher than most uses,
but not as  high  as those for which  air  blast equipment is used.  Assuming
protective  clothing  is  worn,  the margins of safety are all greater than
500, and the cancer  risks  are approximately 1.9x10"^ for  ornamentals,
1.2xlO~5 for Christmas  trees, and 1.2xlO~4  for forestry.
                                     72

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The number of people who would be exposed to these risks is high for
homeowner ornamentals (estimated at 75,000), medium for Christmas trees
(10,000) a-nd low for forestry (ioOD).

Potentially high economic losses would occur if any of the three uses  in  this
category were cancelled, since alternatives are not available for control of
wood borers.  Although economic impacts to the affected industries and the
public could not be quantified, the impacts would be minor in cooler climates
where cultural, non-chemical control measures are practiced.  Southern forest
owners would be hard-hit economically, since they rely heavily on chemical
control.  Honeowners in many areas could suffer aesthetic and economic losses
in forested areas.

Taking all of these considerations into account, EPA will take the following
actions for each of these uses:


            Forestry:

Cancellation of the forestry use is I not warranted, since the benefits  are
high and the risks can be sufficiently reduced by other mechanisms, such
that the benefits will exceed the risks.

The Agency believes that although the cancer risk is an upper-bound, (1.2 x 10~4)
it is prudent to restrict the use and to require protective clothing.  These measures
would not significantly increase costs associated with forestry uses,  but would
decrease the possible cancer risks.  Applicators and mixer/loaders will be
required to use the same protective clothing as with cunaercial ornamentals.

In addition, registrants will be required to update their product labels  to
meet current standards. Labels must describe proper handling and disposal,
symptoms of poisoning, practical treatment in the event of poisoning,  and. other
warning statements appropriate for the product's toxicity category.

            Homeowner Ornamentals;

Cancellation of this use is not warranted since the benefits are high  and the
benefits will exceed the risks if less stringent measures are taken.
                                     73

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The absolute  risk levels fron this use are the lowest in the foliar
application use  group,  but the number of persons who might  be exposed  to
these  risks is high and is of concern to the Agency.

A protective  clothing requirement would not increase the costs of  this
use significantly,  but would significantly reduce the possible cancer  risk.
Therefore, the following protective clothing is prudent and will be required
for applicators:  long—sleeved shirt,  long pants, waterproof gloves,  full
foot covering, and  a head covering such as a hat,

Although  the  Scientific Advisory Panel recommended restricting this use to
certified applicators,  EPA has considered this carefully and does  not  believe
it is  reasonable or necessary, for the following reasons: 1)  The Agency's
revised estimate of cncogenic risk is 1.9x10"^.  The revised MDS is more than  .
3500.  In the PD 2/3 the risk estimate was 2.5xlO~5 and the MDS over 100.
(The difference  is  due  to estimating exposure based on a final use  concentration
of 0.06%  as prescribed  by the existing labels versus the 0.5% assumed
in PD  2/3)  2)   The requirements are easy for hojeowners to follow.  3) The
benefits  of the  use would be significantly reduced by such  a requirement,
since  pest control  firms are often unwilling to take jobs that d'o not  include
care of an entire lot.   Thus, even though the .homeowner's pest problems may  »
be limited to one or a  few trees,  the cost to a homeowner of obtaining a
professional  applicator's services could be unnecessarily high.  4)  Restricting
the use to certified applicators could result in higher total use of lindane,
since  professionals often use  power hand gun equipment rather than backpack
or hand-pressure equipment.   Therefore,  the use will  not be restricted to
use by certified applicators.

Registrants will be required to update their product labels to meet current
standards. Labels must  describe proper handling and disposal,  symptoms of
poisoning, practical treatment in the event of poisoning, and other warning
stateffi&nts appropriate  for the product's toxicity category.


            Christinas Trees  (foliar application);

Cancellation  is  not warranted, however,  the risks are of concern and can
be mitigated  by  less stringent measures.  In addition,  the benefits  of  this use
are high, due to the lack of alternatives for sane of the critical pests.

However,  protective clothing will be  required as stipulated for commercial
ornamentals   and the use will be restricted to certified applicators.

Registrants will also be required to update their product labels to meet
current standards,  Labels must describe proper handling and disposal, symptoms
                                    74

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of poisoning, practical treatment in the event of poisoning, and other warning
statements appropriate for the product's toxicity category.

      3.  Structural Treatments

The only use which currently falls into this category  is structural use  for
treatment of wood borers, powder post beetles, and subterranean termites.
This use of lindane has very high benefits since there are no comparable
alternatives available for this use pattern.

Protective clothing is routinely worn by applicators during structural
application of lindane.  Approximately 8,000 persons apply lindane in
structures.

EPA will not cancel this use since the benefits are so high and since
protective clothing, which applicators usually wear, keeps the risks at an
acceptable level.  For applicators, the MOS is 5435 -when protective clothing
is worn.  The cancer risk is estimated to be 7.4x10"^ while the number
of applicators exposed is approximately 8,000.
                                                       i
Since a requirement to wear protective clothing would insure that the risks
remain at acceptable levels, would not negatively affect the benefits, and
is consistent with current use practices, the Agency will require that
applicators wear protective clothing as described under commercial ornamentals.
In addition, respirators (approved by OSHA regulation 29 CFR 1910.134) will
be required for applicators working in enclosed areas such as crawl spaces.

In addition, registrants will be required to update their product labels to
meet current standards. Labels must describe proper handling and disposal,
symptoms of poisoning, practical treatment in the event of poisoning, and
other warning statements appropriate for the product's toxicity category.
Although it is expected that the use will tend to limit itself to professionals
for practical reasons, EPA will restrict this use to certified applicators,
because of the importance of correctly identifying the species of wood
infesting beetle prior to treatment, the specific control measures needed to
be undertaken, and the fact that occupants can be exposed to treated areas.

Post-treatment exposure levels are low enough that the Agency feels no actions
are required to reduce them.  The estimated margin of safety is 7246.  The
upper-limit cancer estimate is 3x10"^.


      4.  Dip Applications

The uses which fall into this category include hardwood logs, dog dips, and
dog shampoos.  Although all may be considered dip applications in that the
                                   75

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treatment  involves  immersion into a  liquid' formulation,  the actual mechanism
of  immersion differs  between these uses  and affects  the  levels of exposure
associated with  each  (EPA 1982b).

In general, these uses  involve higher exposure  to applicators than other
application methods except for the above-shoulder sprays.  Unlike most of
the other  use groups, however, exposures differ markedly between the uses
within  this group.  Some involve  exposure to homeowners, possibly including
children,  while  others  are industrial uses.  Thus,  the exposure and risk
estimates, as well as the relevant regulatory considerations, must be
considered individually.

EPA will require special disposal instructions  for lindane dips used in large
quantities, such as the hardwood  and livestock  uses.  However, smaller quantities
such as are used for  dog dips in  veterinary establishments will not be subject
to  these requirements.


         Hardwood Logs  and Lumber;                                   .            »

For this use, EPA estimated risk  under the assumption that protective
clothing is worn.  Actual monitoring has shown  that  long-sleeved
shirts, long pants, rubber aprons, waterproof gloves and hard hats are
routinely  used  (EPA 1982b).   Estimates show the .MDS  to be greater than
1000 and the upper-bound cancer risk to  be around 4x10""* with these protective
clothing measures*

Approximately 840 people are estimated to be exposed.  The cancer risk
is about 3.6xlO~4.  The MDS for this use is 3846,  which  is very adequate.

The economic benefits of this use are high.   The  approximate cost if lindane
were cancelled and no alternative were available  would be $240 million
annually.  However, a more reasonable estimate  of  expected losses is $500
thousand annually; this estimate  is  based on the  assumption that endosulfan,
an alternative to lindane,  would  be  available and  equally effective.

Cancellation is  not warranted since  the  benefits  of  this use are significant,
the number of applicators at risk is low,  and the  primary alternative
(endosulfan) has potentially equal or greater risks  associated with it
(please refer to discussion of endosulfan as an alternative for the pecan
use in Section VI., E.,  1.).

Protective clothing keeps the risks  adequately  low in relation to the high
benefits.  It would not significantly increase  the costs of this use, is
already routinely used  by most of the industry, and  is a prudent measure for
a use which involves exposure to  potentially large, quantities of lindane.
Therefore, protective clothing will  be required for  persons in areas where
splashing, or handling  of wet. wood,  is expected. The clothing is described
under commercial ornamentals.   Hard  hats are not  considered necessary as a
safety requirement for  protection against lindane, although SPA recognizes
that they  are often worn for other reasons.
                                  76

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Registrants will be required to update their product labels to meet current
standards.  Labels must describe proper handling and disposal, symptoms of
poisoning, practical treatment in the event of poisoning, and other warning
statements appropriate for the product's toxicity category.

It would not be useful to restrict this use to certified pesticide applicators,
because the applicators are not significantly exposed.  Rather, the workers
in the area of lindane dip are nest exposed and are therefore the ones needing
protection through protective clothing, as required above.

         Dog Dips;

EPA prepared estimates of risk from dog dips for three groups: veterinarians,
home applicators, and those who are exposed to the dog "post-treatment".

Risks associated with post-treatment exposure are acceptably lew.  Without
protective clothing, the MOS for general toxicity and fetal effects is greater
than 58000.  The estimated upper-bound cancer risk is 4.2xlO~7.  Also,
there is not a significant risk to applicators of general, fetal, and     .       ,
liver toxicity, since the MOS is well over 8000 with or without protective
clothing.  Therefore, for regulatory purposes, EPA is only concerned about
the possible cancer risk to people who are exposed during application.

EPA's estimates of the cancer risk to veterinarians assumes that they would
treat approximately 26 dogs per year with lindane dips..  Under this assumption,
the upper-bound cancer risk is estimated to be 4.2xlO~6 if protective
clothing is worn.  Protective clothing in this case is assumed to include
long—sleeved work shirt, long pants, elbow length waterproof gloves, and
an waterproof apron.  Approximately 130,000 veterinarians (and their assistants)
are expected to treat dogs with lindane dips each year.

The possible cancer risk to hone applicators of lindane dog dips were not
calculated separately.  However, the Agency assumes that the risks to home
applicators are not a significant concern, since they would be exposed to far
fewer applications than veterinarians (perhaps 1-2 times per year, as opposed to
the estimated 26 times per year for veterinarians).

One additional coasideration, unique to this use, is the problem of acute
toxicity to domestic animals.  Seven dog deaths were reported between 1966 and
1978 resulting from use of these dog washes, but the Agency assumes that the
number of actual deaths is higher than the number of reported deaths.   In
addition, at least nine dogs were reported to have been made very sick as a
result of treatment with the dips during the same period.  Whether lindane alone
is the cause is difficult to establish, because the dips are usually formulated
with other chemicals as well.  However, the case histories show that dog deaths
usually resulted from misuse or carelessness,  such as not diluting the dip
sufficiently.  When dogs are treated with dips for scabies, they are often quite
ill to begin with; it is probably to be expected that a certain number would
die as a result of a combination of their ocor health and exoosure to the dio.
                                    77

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Therefore, all  labels will  be  required  to  include a statement warning that
"improper dilution of this  product  could cause serious injury to your pet".

The benefits of  this use are very high  for that proportion which is used to
treat scabies,  because  there are no equally effective alternatives for that
use. Against other pests such  as ticks  and fleas the use has low benefits,
(that is, cancellation  would not cause  significant economic losses) since
there are numerous alternatives in  the  same price range as lindane.
                                        i
Taking these factors into consideration, EPA believes the following actions
for dog dip uses of lindane will insure that the benefits exceed the risks of
this use.

Cancellation of  the dog dip for control of scabies (which is caused by mites)
is not warranted, considering  the high  benefits.  The cancer risks to veter-
inarians can also be significantly  reduced with the use of simple protective
clothing measures.  Therefore, the  following protective clothing will be
required for veterinarians: elbow-length waterproof gloves, a waterproof
apron, and(unlined, waterproof boots.

Use of dog dips  to control  pests other  than mites, such as fleas and ticks,
will be cancelled because of the low benefits of this use (i.e., avail-
ability of registered alternatives) and because of the cancer risk to
applicators.  To prevent use for pests  other than mites, labels will specify,
"for treatment  only of  mites;  treatment of other pests is prohibited."

Registrants will be required to update  their product labels to meet current
standards.  Labels must describe proper handling and disposal, symptoms of
poisoning and practical treatment in the event of poisoning (for both the
applicator and  the dog), and warning statements appropriate for the product's
toxicity category.

Although the Scientific Advisory Panel  suggested restricting these products
to certified applicators and veterinarians, EPA does not believe these
measures are necessary.  The reasons are that the MOS for general and fetal
toxicity are more than  adequate, and the cancer risk to hone applicators
should also be minor, since home applicators are expected to use these products
significantly less often, over a lifetime,  than veterinarians. (Readers who
wish to examine  the exposure assumptions which lead to these risk estimates
will find them  in Appendix  III.)

As with all lindane products which  are  available to the general public, the
Agency is concerned about misuse by children.  These products will therefore
be required to  promptly comply with the EPA child resistant packaging
regulations, which require  child resistant packaging in those cases where
the active ingredient concentration is  greater than 6.5% (46 FR 15104).
For the same reason, labels must include a  statement that "children should
not be allowed  to apply or  handle this  product."


         Dog Shampoos:

EPA prepared estimates  of exposure  and  risk from use of lindane dog shampoos
                                   78

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Risks frcm post-treatment exposure are sufficiently  lew  (see Table  6)  that
the .Agency believes no action  is necessary to  further  reduce them.
Although the margin of safety  for applicators  is well  over 1000,  and
therefore more than adequate,  the estimated upper-bound  cancer  risk is high
for a household use.  Specifically, the upper-bound  cancer risk for hone
applicators is estimated at 2.2xlO~5, assuming use of  one  to tv«lve
times per year.  The Agency believes that this risk  is especially significant
when compared to the benefits  of this use, which are negligible since  there
are many alternative flea shampoos available in the  sane price  range as lindane
shampoos.

The Agency was unable to estimate the number of persons  who would be exposed to
these risks.  However, data from a 1977 survey by Hooker Chemicals  showed 16,700
"units" of lindane pet shampoos sold in that year (Correspondence,  1982b).
This may be taken as a reasonable estimate of  the maximum  nunber  of applicators
exposed (assuning each unit was sold to a different  person).  The types of
persons exposed would mostly be the general public.(including children)  and
scene veterinarians.

Having considered the preceding factors,the Agency has decided  to take the
following actions regarding lindane dog shampoos:

Cancellation does not seem to  be warranted since the risks could  be mitigated
by less stringent measures.  EPA therefore considered  a  nunber  of other ways to
reduce the risk, but most were impractical.  Altering  the  product concentration
would make almost no impact on the exposure estimates, since we are already
assuiung a ten-fold dilution with water when the shanpco is in  use.  Protective
clothing requirements are not considered reasonable  for  homeowners,  since
•waterproof gloves and aprons are not readily available,  and could not  be
expected to be worn by the average hone applicator.  EPA also considered
limiting the number of times the shampoos can  be used, as  a way of  reducing
the cancer risk.  However, to reduce the risk  to an  acceptable  level,
applications would have to be  limited to less  than once  annually.   This  is
clearly impractical.  Label warnings were considered,  but  do not  sufficiently
alleviate the concern that children may misuse the product, since they are
less likely to understand .and  follow directions regarding  proper  dosages.

Taking all of these considerations into account, EPA finds it necessary to
restrict the use of lindane shampoos to certified applicators (veterinarians
would not be precluded from using these products under this requirement; see
section 171.4(e) of the SPA Applicator Certification Regulations).   The Agency
believes that this requirement is necessary even though  other cog products
reviewed (dips) do not require this restriction.  This is  primarily because
if the upper-bound cancer risk estimated for shampoos  is correct, it
is unacceptably high when compared with the almost negligible benefits of  this
use.  Furthermore, as explained above, EPA cannot reduce the risk by other
means.  The other dog products do not entail such high risks (see Table  6)  and
therefore need not be subject  to the same measures (see  Appendix  III for an
explanation of the exposure assumptions leading to these risk estimates).

EPA will require applicators to wear protective clothing,  including waterproof
gloves and aprons.  Such clothing will reduce  the upper-bound cancer risk
to'4.5x10-6.  The protective clothing requirement could  be easily met  by
those allowed to buy and use lindane shampoos,  since veterinarians


                             4    r  79

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usually  have waterproof gloves and aprons.

Registrants of dog shanpcos will also be required to update their product
labels  to meet current standards.  Labels must describe proper handling  and
disposal,  sympccms of poisoning and practical treatment in the event  of poisoning
(for  the dog and the applicator),  and other warning statements appropriate  for
the product's toxicity category.


      5.  Enclosed Area Sprays;

The fact that respiratory exposure is the main route of exposure  distinguishes
enclosed area sprays from other lindane uses.

Exposure and risk to applicators are lower than the previous  use  groups
discussed (overhead sprays, crawl space treatments, and dips).  The margins  of
safety are more than adequate: approxiamtely 3000 or more  even if protective
clothing is not worn.   Upper-bound cancer risks (again assuming no protective
clothing)  range from a high of 9.2x10"^ for fumigation devices, to a  low of
1.5x10-5 for uninhabited building and storage bin sprays.

There are numerous alternatives available for all of the enclosed-area  spray
uses. Their benefits are estimated to be rather low.

Approximately 840 people apply lindane in uninhabited buildings and storage
bins. The Agency was unable to obtain estimates of the number of  persons who
apply moth sprays or use fumigation devices.

Taking all of these considerations into account, the Agency has decided to  take
the following actions-for these.uses:


          Moth Sprays;

The benefits of this use are low,  and the risks are not unacceptable.   Specifi-
cally the margin of safety for general toxicity is greater than 3000, whether
or not protective clothing is worn.   The maximum cancer risk  is estimated at
5.6x10-3 without protective clothing,  and 5xlO"5 with protective  clothing.
These estimates do not assume the use of respirators even  though  respiratory
exposure is the- most significant route in this case.  Use of a respirator would
reduce respiratory risk by a factor of 10.   This is why the risk  estimates
assuming protective clothing is worn (excluding a respirator)  are not significantly
different from those when protective clothing is not worn.  Roughly 1000-3000
persons  are exposed annually to lindane moth sprays.

Risks to employees following moth spray treatments are not of sufficient
concern  to warrant protective measures, especially since most dry cleaning
establishments have strict ventilation requirements which  would be expected

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to aid in dispersing any lindane vapors which may be present.  Also, the
National Institutes of occupational Safety and Health (NIOSH) have established
allowable air levels for lindane in dry cleaning establishments, which are
sufficient without further action by EPA.

In conclusion, the benefits of moth spray products are lew, but the risks to
applicators are not unreasonable and cancellation is not warranted.

Although EPA acknowledges that protective measures may not be necessary if  the
cancer risk is significantly lower than estimated, the potential cancer risk
can be easily and inexpensively reduced to a more acceptable level by decreasing
the respiratory exposure.  Therefore, EPA will require applicators to wear
MSHA/OSHA-approved cartridge respirators during application of lindane moth
sprays.

Also, registrants will be required to update their product labels to meet
current standards.  Labels must state that this product should only be used in
a well-ventilated area.  Labels must describe proper handling and disposal,
symptoms of poisoning, practical treatment in the event of poisoning, and
other warning statements appropriate for the product's toxicity category.


            Fumigation Devices:

This use entails no significant risk to honeowners of causing general, fetal,
or liver effects.  The cancer risk to homeowners associated with the indoor
use of. these devices is 9.2xlO~4.

The benefits of these uses are negligible, since there are numerous alternative
products which kill the same spectrum of insects.

The Agency was not able to estimate the number of people exposed to these
products, but fumigation devices are available to the general public.

EPA made many attempts to consider ways of reducing the risks associated with
this product, and invited suggestions from the registrant.  However, the risks
associated with these products are based- on data submitted by the registrant and
on reasonable assumptions of ventilation (Memo, 1982i).  The potential cancer
risk associated with the indoor use of smoke fumigation devices is unacceptable.
Therefore, the Agency will cancel the indoor use of smoke fumigation devices.
                                  81

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            Uninhabited Building and-Storage Bin Sprays;


The benefits cf  this  use are lew but the risks are also low.  Specifically,
applicators' maximum  risk of cancer is 1.5x10"^ if protective clothing  is
not worn, and  6.4x10"^  if it is worn.   Margins of safety  for  acute and
fetal effects  are  greater than 50,000  with or without  protective clothing.

The Agency.was unable to obtain estimates of the number of people who
could be exposed to lindane through this use.

Taking the above into consideration, the Agency believes  the  risks of these
uses are not unreasonable,  so there is no justification for cancelling  or
restricting than.

Registrants of these  uses will be required to update their product labels
to meet current  standards.   Labels must describe proper handling and
disposal,, symptoms of poisoning, practical treatment in the event of
poisoning, and other  warning statements appropriate for the product's
toxicity category.


      6.  Dusts

Uses which fall  into  this category include planter box seed treatment,  and
dog dusts.  Exposure  and risks from these uses are lower  than those associated
with the use groups previously discussed, namely above-shoulder sprays,
dips, and enclosed area sprays.

Pcst-trea-tenent exposure estimates were calculated for  persons sowing treated
seed or being  exposed to dogs that have been treated with lindane dust.  Risks
frcm post-treatment exposure are sufficiently low that the Agency does  not
consider it necessary to take action to reduce them.

Specific considerations relevant to applicator risks from the dust uses of
lindane are discussed below.

         Seed  Treatment;

Applicator risks frcm this use are moderately low. The margin of safety for
toxic^effects  is 5000 if protective clothing is worn.  The cancer risk is
3xlO~5 if protective  clothing is worn.  The number of applicators potentially
exposed to these risks  is estimated at about 130,000.

SPA dees not consider it reasonable to cancel this use since  the risks  are
relatively low and the  benefits, although unquantifiable, have been attested
to as significant  by  numerous users.

The Agency acknowledges that the cancer estimates are  conservative, and that
if the risks are actually lower than estimated they may not be unreasonable.
However, protective clothing is a prudent and inexpensive measure which
would reduce the risks  associated with this use without adversely affecting

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the benefits, and would insure that the risks  are outweighed by  the benefits.
Therefore, the Agency will require the following protective  clothing during .
luanual seed treatment operations: long sleeved shirt,  long pants,  gloves,
and a disposable paper dust mask covering at least one-third of  the face.
However, no protective clothing will be required during automated  seed
treatment operations, closed-system seed treatment, or seed  sewing,  since
exposure associated with these activities is negligible.

The Agency will also require, for camercial dust uses, the  following
precaution on the label: "This product should  be applied  in  a well-
ventilated area".

All registrants will be required to update their product  labels  to meet
current standards.  Labels must describe proper handling  and disposal,
symptoms of poisoning, practical treatment in  the event of poisoning,
and other warning statements appropriate for the product's toxicity
category.

The Agency does not consider that the risks associated with  this use are
substantial enough to justify restricting the  use to certified applicators.


            Dog Dusts;

Applicator risks of general toxicity and fetal effects are low:  the  margin  of
safety for toxic effects is greater than 2500  without  protective clothing.
The upper-bound cancer estimate is 6.4x10"^ if protective clothing is
not worn. This is reduced to 1.4x10""^ if protective clothing is  worn.
The number of persons potentially exposed to these risks  could not be
estimated, but the products are available for  use by the  general public.

The FIFRA Scientific Advisory Panel recomended cancelling these products.
The Agency does not believe cancellation is necessary, since less  stringent
measures would reduce these risks.enough to insure that they are not
unreasonable, and would not adversely affect the benefits of the use.
However, the Agency is concerned that children may be  excessively  exposed
either due to misuse or mishandling of a household pesticide product,  or
via the contact with treated pets.   Since there are alternatives to  this
use pattern and since the benefits are low, the Agency will  restrict
this use to certified applicators.   As with dog shampoos, veterinarians
would not be precluded fron using lindane dog dust products  (see Section
171-.4(e) of the EEA Applicator Certification Regulations).

In addition, the Agency will require the following label  reccrmendation:
"this product should be applied in well-ventilated areas".

Registrants will also be required to update their product labels to  meet
current standards. Labels must describe proper handling and  disposal,
symptoms of poisoning, practical treatment in  the event of poisoning,
and other warning statements appropriate for the product's toxicity
category.

                                      r\ -»
                                      OJ

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      7.  3elow-Shoulder Sprays

This use group  includes  cucurbits,  and the stump/slash  treatment of
Christmas trees.   Risks  frcm these  uses tend  to  be  lower than from the
use groups previously discussed.

         Cucurbits;

The risks from  this use  are very  low.   The margins  of safety for toxic effects
are greater than 28,000.   The upper-bound  cancer risk is 3.7x10""^
without protective clothing and 1.9x10"^,  if  protective clothing is worn.
The estimated number  of  people exposed to  these  risks is about 950.

Since these risks  are not unreasonable,  the Agency  does not intend to cancel
or restrict these  products except that registrants  will be required to update
their product labels  to  meet current standards.  Labels  must describe proper
handling and disposal, symptoms of  poisoning, practical treatment in the
event of poisoning, and  other warning  statements appropriate for the product's
toxicity category.


         Christmas Trees (stump/slash  application)

The estimated general toxicological risks  from this use are also low, and
are clearly, exceeded  by  the benefits if appropriate measures are taken.  The
margin of safety is greater than  250 with  protective clothing.  The maximum
cancer risk is  3x10"^ with protective  clothing.   Approximately 10,000
applicators are exposed..

The cancer risk frcm  this use is  not acceptable  to  the  Agency.  However, the
Agency believes this  to  be a valuable  use  of  lindane.   Therefore, cancellation
is not recommended; however,  this use  will be restricted to application only
by certified applicators.   In addition,  protective,  clothing will be required
as described under commercial ornamentals.

Registrants will be required to update their product labels for this use, to
meet current standards.   Labels must describe proper handling and disposal,
symptoms of poisoning, practical  treatment in the event of poisoning, and other
warning statements appropriate for  the product's toxicity category.
                                     84

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                                    85
      8.  Pre-Plant Soil Applications

The only currently registered use which falls into this category and was
reviewed by the Agency is pineapples.  The sugarcane use  (currently used
only under the Section 18 emergency use provisions) was not separately
reviewed, but is expected to involve similar exposure to  the use on pineapples
and will therefore be subject to the same requirements.

          Pineapples

Pre-plant soil applications in general involve very low exposure to applicators.
Even if no protective clothing is worn, the margin of safety for toxic
effects is greater than 1,000,000.  The maximum cancer risk is
1.5xlO"~H.  These risks are negligible both in absolute terms and relative
to the benefits.  Therefore, the Agency does not intend to cancel or restrict
this use.  However, registrants will be required to update their product
labels to meet current standards. Labels must describe proper handling and
disposal, symptoms of poisoning, practical treatment in the event of poisoning,
and other warning statements appropriate for the product's toxicity category.


      9. Other Household Products

The uses which fall into this category are flea collars, shelf paper, and
household sprays.  All of these uses have low benefits, but also low risks.
Specifically, the margins of safety for toxic effects are all greater
than 1000.  The highest cancer risk estimated for any of these products is
4.9xlQ~6 for the household spray applicators.  Specific estimates for the
other uses may be found in Table 6.

EPA attempted to estimate whether cumulative exposure to lindane household
products might be a significant concern.  Although no quantitative estimate
could be developed, EPA believes the likelihood of significant cumulative
exposure is remote.  Lindane holds such a small portion of the household
pesticide market (less than 3%)  that it is unlikely that a household would
purchase two lindane products for different uses.  Also, the season or
site of application would be likely to differ. (Savage et al., 1979;
Correspondence, 1982a).

The FIFFA Scientific Advisory Panel and the U.S. Department of Agriculture
recommended cancelling these uses.  However, EPA does not currently believe
there is now sufficient justification for cancellation.  The highly con-
servative_estimates of risk noted in PD 2/3 were 2xlO~4 (flea collars)
and 4xlO~5(shelf paper).   The corrected estimates of risk are 4.2xlO~6
and 2.1xlO~6 respectively.*

Considering these risks,  the Agency believes there is justification only for
minor restrictions on lindane household products.  These include the restriction
that children should not be allowed to handle or use the products, and that
children and pets should not be allowed in treated areas until surfaces are
dry.  Statements to this effect will be required on all lindane household
products.

All registrants will also be required to update -chear product labels to meet

   * Lindane floor wax uses have been voluntari.ly v ithdrawn from the market
     and were therefore not considered in this 
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current  standards. 'Labels must describe proper handling  and  disposal,  symptoms
of poisoning,  practical treatment in the event of poisoning, and other warning
statements  appropriate for the product's toxicity category.  In the case
of household products, this will specifically include  the  following label
statement:  "Do not  allow children to apply or handle  this product".

       E«_  Summary Conclusion On Dietary Risk

There are a number of tolerances for lindane (40 CFR 180.133) ranging  fron
0.01 pptn (pecans) to 7 ppm in fat of meat animals,   using  the conventional
method of total maximum residue contribution (TMRC)  calculation a 0.78
mg/day intake  can be computed.  In addition, there are several action
levels established for lindane including 0.3ppn in milk  fat.  Both PD
2/3 and  PD  4,  however, have used figures derived fron  FDA  Total Diet
Composites, collected over several years, to estimate  dietary exposure.
In the PD-4 the_Agency now estimates the dietary exposure  to be between
0.3 and  1.6x10"^ mg/kg/day.  The estimated cancer risk assessment for
these exposure figures range from 3.3xlO~6 to 1.7xlO~5,  depending on
whether  all the market basket data are considered or only  those of the
last several years.                                       i                    *

The Agency does not  consider these risks unacceptable  for  the following
reasons:  (1) because of the uncertainty about lindane's  oncogenic potential
as a human oncogen as discussed in this PD (Section  II.  A.2), (2) because
residues on food seem to be declining as shown by the  market basket
survey,  and (3)  because the Agency used a conservative model for estimating
risk which produced  figures representing the upper bounds  of the estimated
risks.   Moreover, the Agency has good reason to believe  that lindane
residues, if any, on food are not necessarily a result of  direct agricultural
applications to a particular crop.  Thus, cancellation  of agricultural
uses would  not likely eliminate residues on food items.  To  resolve this
issue, the Agency will place special anphasis on the reevaluation of
tolerances and action levels presently in effect.  These reevaluations will
take place  during the Agency's Registration standard program for lindane.
At that  time,  the Agency will again assess the dietary exposure and the
actual sources of lindane in the food supply.  At that time  it will
consider any further regulatory action that might be necessary to reduce
dietary  exposure and risk.

     EPA also  realizes that residue levels for lindane at  or about tolerance
levels,  i.e.,  exposures 'commensurate with TMRC, would  not  be considered an
acceptable  risk, and that dietary exposure should not  exceed about 1.6xlO~5
mg/kg/day.  It therefore follows that monitoring the food  supply for samples
which exceed established tolerances (as is the case  for  most pesticides) is
not in itself  sufficient in the case of lindane.   EPA  will,  therefore, evaluate
FDA's and USDA's data on regulatory compliance samples as  well as the Total
Diet Composite samples.   This will further serve to  assure the Agency that
the assumptions made with respect to lindane's presence  in food are essentially
correct  and that dietary exposure will not substantially increase.  In addition
this continuing surveillance data will be used in re-evaluating the tolerances
and action  levels.
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   F.  Risk/Benefit Considerations Which Apply To All Lindane Products


Besides the use-specific risks and benefits discussed in the preceeding
section, the Agency has concerns which apply to all lindane products. These
considerations are discussed in this section.


      1.  Possibility of  Accidental Misuse

First, the Agency is concerned about general misuse of lindane, although seme
acute effects are irreversible effects are more serious at high levels of exposure
(convulsions and death can result). Because misuse has resulted in high levels
of exposure and serious adverse effects in the past, the Agency feels that all
lindane products should be required to meet certain basic labeling standards
which would mitigate the chance of misuse by informing consumers and
applicators of how to properly use lindane products. Labeling improvements are
a particularly desirable type of requirement since they will not adversely
affect the benefits of the continued use of these products.

Therefore, all household products must include the following statement: "Do not
allow children to handle or apply this pesticide product".  Also, all registrants
will also be required to include information on the label regarding
proper handling and disposal, symptoms of poisoning, practical treatment in
the event of poisoning, and other warning statements appropriate for the
product's toxicity category.  All labels must disclose all active ingredients
and the percentages in which they occur.


      2.  Possibility of Aquatic Contamination

Although EPA is not aware of current problems with lindane contaminating
aquatic environments, the potential exists, if lindane were to get into
such environments through routine practices.   Therefore, EPA will
prohibit aerial application of lindane, as suggested by the U.S.
Department of Agriculture, since it could result in significant
runoff and drift.  EPA will also deny any future requests to register
lindane for direct application to aquatic environments.


G. Voluntary Actions To Vvhich Registrants Of Technical Lindane Have Agreed;
   Mutagenicity Testing

The Agency has determined that there is an outstanding and important question
of whether lindane is a mutagen, and believes that the lindane mutagenicity
data base should be completed.  In addition, further information about lindane1s
mutagenicity may explain whether lindane acts through a genotoxic carcinogenic
mechanism.

In order to accomplish the development of additional mutagenicity data on
lindane, an informal, voluntary agreement has been reached with the registrants
of technical lindane represented by CIEL.   The Agency will issue a letter
pursuant to section 3(c)(2)(B) of FIFRA to all registrants of lindane indicating
that additional mutagenicity data are required.  The voluntary agreement will
likely satisfy the provisions of 3(c)(2)(B) for joint development of data.
The short term tests which CIEL has agreed to sponsor are as follows: (i to
iii).

                                   8?

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            i.   In Vitro Gene Mutation Testing in Mamnalian Cells

This  type  of  assay was agreed upon because the only validated test types  are
chcse conducted in bacterial cells.   Although there are potential problems  •
with  the exogenous activation for such in vitro assays, the lack of a
comprehensive,  validated series of tests by the more insensitive in vivo
approach leaves in vitro testing in mammalian cells as the only option.  (It  is
also  more  rapid,  more sensitive, and less costly).   One purpose of this  test
is  to answer  questions about lindane's metabolic activation;  specifically,
modulation of  secondary enzyme activity in mammalian systems,  if feasible.
Exogenous  activation from the CFI mouse strain will be employed.  If valid
positive results  are found in in vitro tests, one then may pursue more pro-
ductive lines  in  vivo, depending on the particular effects generated.

           ii.   In Vivo, Oral and Parenteral Assay for Sister  Chromatid Exchange

This  testing  is important in order to answer questions about  lindane's activation
outside the liver, coincident with its unresolved chromosomal effects.          »
Comparison of  oral vs. parenteral administration of the test  compound could
help  resolve  the  issue of "anaerobic" metabolites potentially active in
cncogenesis and/or mutagenesis.

         iii.  In  Vitro Test in Mammalian Cells Under Anaerobic Conditions

The purpose of  this assay -would be to shed light on the differences between
in vitro and  in vivo conditions.

Because this  type of assay is not standardized at this time,  its completion
will  depend on  whether or not an adequate test protocol can be agreed upon
by SPA and CTEL.

           iv.   Other Tests

Other tests which have been recommended to CTEL for completion would also help
to fill data gaps in the current rautagenicity data  base.   However,  since these
are not necessary for the primary goal of completing the RPAR,  CIEL will be
cortpleting these  tests over a period of several years as a secondary priority
to the tests discussed above.

The following  tests are those recommended as a second priority:
                                     88

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Micrcnucleus Test in vivo;

Sister chromatid Exchange _in vitro, using CKO cells, or any
other cell type with a growing data base;

Stimulation of Hepatic Pre-Necplastic Foci:

Unscheduled DNA Synthesis (DNA-repair) test in rodent
hepatocytes (HPC-UDS).

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VIII.  SUMMARY OP PECULATOR* POSITION
                   90

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A.  Requirements for Above-Shoulder Sprays; AIR-BLAST OR POWER-HAND-GUN

    1.  ALL air-blast and pcwer-hand-gun uses will be subject to the
        following requirements:

        0 Restriction to use by certified applicators only

        0 Protective clothing will be required for
          (See VII E. 1. Coranercial ornamentals)

        0 Labels must be updated as described in Chapter VIII, J.
          (see "Requirements for All Uses). •

    2.   USE-SPECIFIC requirements for air-blast and power-hand-gun
         uses are as follows:

         Ornanentals;

        0 Restriction of use (connercial application) to certified:applicators,

        8 Protective clothing required.

          Avocados;

        0 Restricted to use by certified applicators only.

        0 Protective measures required for applicators (See VII E. 1.
          Connercial ornamentals)

          Pecans:
        0 Restricted to use by certified applicators only

        0 Protective clothing required for applicators (See VII E. 1. Commercial
          Ornanentals)

          Livestock;

         0 Restriction of use to certified applicators only

         0 Protective clothing required (see VII E. I. Coimercial ornamentals)

          Other Uses:

          0 Protective clothing for other air blast or power hand gun
       uses must be similar to that for the specific uses described here.
       Specifically: waterproof clothing or roof-type shelters will be
       required unless EPA's Registration Division determines that it is
       infeasible for the particular use.  At a minimum, long-sleeved
       shirt, long pants, waterproof gloves, full foot covering, and
       appropriate accessories for the type of use will be required.
                                    91

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S_L  ?f(?J^r:rne.rIts  "r Above—Shoulder S_grays_:_ Backpack or Hand Pressure
    Equipment

    All_uses:

    0 Protective  clothing  required  for applicators: long-sleeved
      shirts,  long pants,  impermeable gloves,  full foot covering, and
      head covering such as  hat  or  bandana.

    0 Protective  clothing  required  (see VII. E.  1. commercial ornamentals).

    0 Labels must be updated as  described  in Chapter VIII, J.
      (see "Requirements for All Uses").

    0 Forestry use restricted to certified applicators.

C.  Requirements  for Structural  Uses

    0 Use restricted to certified applicators.

    0 Protective  clothing  required  (See VII. E.  1. Contnercial ornamentals).

    0 MSHA/OSHA-approved respirators for applications  in enclosed areas
      such as crawl spaces.

    0 Labels must be updated as  described  in Chapter VIII, J.
      (see "Requirements for All Uses").

D.  Requirements  for Dip Applications

    0 Special disposal instructions will be required for lindane dips
      used in large quantities.

    0 For all lindane dip  uses,  labels must be updated as described
      (see "Requirements for All Uses") in Chapter VIII, J.

    Hardwoods:

    0 Persons working in areas where splashing or handling of wet
      wood is expected, are  required to wear protective
      clothing as described  in VII.  E. 1.  Commercial ornamentals

    Dog Dips:

    0 Protective  clothing  required  for applicators: long-sleeved
      shirts, long pants,  elbow  length impermeable gloves, and
      waterproof  aprons;

    0 Labels must include  following statement: "Improper dilution of this
      pesticide product could cause serious injury to your pet".

    0 Products with concentration of a.i.  greater than 6.5% must
      have child  resistant packaging.

    0 Labels must include  the statement: "Children should not be
      allowed to  handle or apply this pesticide  product".

    0 Labels must specify: "For  treatment  only oi: mites;; treatment of
      other pests is prohibited."

                                 92

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    Dog Shampoos:

    0  Use will be restricted to certified applicators and veterinarians.

    0  Protective clothing required for applicators:  long-sleeved shirts,
       long pants, full foot covering, elbow-length waterproof gloves,
       and waterproof aprons.


E.  Requirements for Enclosed Area Sprays

    Moth Sprays

    0  Applicators will be required to wear MSHA/OSHA approved
       cartridge respirators.

    0  Label updates as described in Chapter VIII, J.
       (see "Requirements for All Uses")

    Fumigation Devices

    0  Cancel indoor use.

    Uninhabited Building and Storage Bin Sprays;

    0  Labels must be updated as described in Chapter VIII, J.
       (see "Requirements for All Uses")


F.  Requirements for Lindane Dusts

    0  Labels for ALL lindane dust products must be updated as described
       (see Requirements for ALL Uses) in Chapter VIII,  J.

    Seed Treatment:

    0  Protective clothing required for applicators during manual seed
       treatment operations:  long-sleeved shirt, long pants,  gloves,
       disposable paper dust mask covering at least one-third  of face.

    0  Required label statement: "This product should be applied in a
       well-ventilated area."

    Dog Dusts;

    0  Use will be restricted to certified applicators and veterinarians.

    0  Required label statement:  "This product should be applied in a
       well-ventilated area."
                                 93

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   G.  Requirements  for Below-Shoulder  Sprays;
       Cucurbits:

       0 Labels must be updated  as described  in Chapter VIII, J.
         (see  "Requirements  for  All Uses")

       Christmas Trees:
       0 Use will be  restricted  to certified applicators.

       0 Protective clothing  required as described in VII. E. 1.
         Conmercial ornamentals

       0 Labels must  be  updated  as described in Chapter VIII, J.
         (see  "Requirements for  All Uses")

   H.  Requirements for  Pre-Plant  Soil Applications

       Pineapples;

       0 Labels must  be  updated  as described in Chapter VIII, J. (see
         "Requirements for All Uses").    '

I.  Requirements for  Other Household Products  (Flea Collars, Shelf Paper,
    and Household Sprays);

       0 Labels must  be  updated  as described in Chapter VII, J. (see
         "Requirements for All Uses")

       0 Required Label  Statement:  "Avoid exposure to children.  Do not
         allow children  to apply or handle this product."

       0 Required Label  Statement  for spray or liquid products:  "Do not
         allow children  or pets  in treated areas until surfaces are dry".

       0 Products with concentrations of active ingredient greater than
         6.5% must have  child resistant packaging.

J.  Requirements for  All Uses

       0 Mutagenicity testing aas  described on pp. 71-72.  NOTE:  A
         voluntary agreement  with  CIEL has been reached for couplet ion of
         first priority  tests 12 months after  publication of the notice
         of availability of PD-4 or agreement  on protocols by CIEL and
         EPA scientists, whichever is the later.  Selection and completion
         of secondary priority tests to be discussed after ccmpletion of
         first priority  tests.
                               94

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All Household Use Products must contain the following label statement:
"Do not allow children to handle or apply this pesticide product".

No Aerial uses

No Aquatic uses

Labelling updates: ALL  REGISTRANTS must update their labels to include:

0 proper handling

0 proper disposal

0 symptoms of poisoning (for applicators, and for pets where appropriate)

0 practical treatment in event of poisoning (for applicators, and for
  pets where appropriate)

0 other warning statements appropriate for the product's toxicity
  category                                                    ;     »
                      95

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               APPENDIX 1;






Garments fron the Secretary of Acriculture
                 	s O

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  November 17,  1980
  Honorable Douglas M.  Ccstle
  Administrator
  U.  S.  Environmental Protection Agency
  Washington, D. C.  20460

  Dear Mr.  Costle:

  This is in response to the U. S. Environmental protection Agency's Notice of
  Determination concluding the Rebuttable Presumption Against Registration of
  Pesticide Products Containing Lindane.

  We  interacted with EPA in developing the biological, economic, and exposure
  information according to the current Memorandum of Understanding between our   *
  two agencies.  Thus,  we are pleased to be able to review and conment on this
  notice and the accompanying position document.

  The opening sentence on Page III-l is incorrectly cited.  The full title of the
  June 1978 report is "Preliminary Benefit Analysis of Lindane prepared jointly
  by  USDA and EPA."  The basic biological and economic information contained in
  the June 1978 and the October 1979 report is the same.  Both of these reports
  were compiled by the joint USDA/States/EPA lindane assessment team.  Because of
  the opening statement on page III-l, our state cooperators have voiced concern
  that their joint efforts may not be utilized by EPA.

  There are areas of agreement as well as issues of concern to us and to the
  cooperating States.  Our comments on these specific items are contained in the
« enclosure which is an integral part of this response,

  The additional time you granted for cur review of this document was very
  beneficial and is appreciated.  We are hopeful EPA will give favorable
  consideration to these suggestions.

  Sincerely,
  Bob Bergland
  Secretary
  U.  S.  Department of Agriculture
  Enclosure

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                                ENCLOSURE
                   SECRETARY OF AGRICULTURE'S  RESPONSE
                 LINDANE NOTICE OF DETERMINATION,  PD 2/3


1. We believe that every effort should  be made to  maintain pest
   control strategies without  causing unacceptable risks to users and the
   public.  We concur with EPA's selection of  regulatory options regarding the
   continued registered uses of lindane on livestock, pineapples, pet washes,
   and commercial ornamentals  with certain label modifications, including
   "Restricted use."

2. We concur in SPA's proposed regulatory options  of cancellation where the
   risks appear to exceed the  benefits.  These include:

   —  Household use associated with shelf paper,  waxes, sprays and smokes
       (fumigation devices) , and the minor use associated with industrial moth
       sprays;

   —  Pet applications including collars, shampoos and dusts?

   —  Insect sprays - uninhabited buildings;  and

   —  Empty storage bins -  fog sprays.

All of these uses involve continuous exposure  for  which there are adequate
substitutes.

3. The precautionary statement, "Do not use lindane products on pregnant or
   young animals," nay be desirable for veterinarians treating household pets.
   However, it may be impractical or impossible, in many cases, to make
   pregnancy determinations  when livestock herds are being treated.  We suggest
   that this statement be modified to be advisory  rather.than a label
   prohibition.

4. We share the EPA's concern  for applicator exposure but would like
   clarification of the exposure calculations  used since this was not explained
   in PD 2/3.  Also, we recommend consistency  in the selection of available
   protective clothing.  The following  label modifications on the use of
   protective clothing might be considered:

   —  Long sleeved shirts and pants.                        '
  V.
   —  Impervious gloves (rubber or necprene)  and  boots.

   —  Wide brimmed hats or  roof type covers over  spraying equipment when
       overhead spraying on  agricultural and/or forestry sites.

   —  Approved respirators  when handling dust formulations and when spraying
       in confined spaces.

   — Impervious (rubber or  neoprene) aprons in those areas where normal
      treatment practices could anticipate splashing of the treatment
      solutions and where aprons do not constitute a hazard around equipment.


                                   98

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5. Livestock  -  As pointed cut in the USDA/State/EPA  benefit report,  lindane
   is often used in combination with other pesticides, primarily  toxaphene,  to
   control pests on livestock.  One of the more popular  combinations is lindane.
   (2%) and toxaphene (44%).  This combination results in  imrediate  control  by
   lindane coupled with the longer residual activity provided by  toxaphene.   In
   developing the final regulatory action for lindane, the regulatory  actions
   taken en toxaphene must also be considered.

   We believe that if the lindane registrations for livestock are retained,  but
   the registered uses of toxaphene are cancelled, the livestock  industry would
   be unable to control certain pest problems.

6. Hardwood Logs and Lumber  - The decision to phase cut this use over a
   2 year period in the absence of effective registered  alternatives
   seems inappropriate considering the extent of anticipated  hazard.   A
   July 28, 1980 letter from southern Forest Experiment  Station at Gulfport,
   Mississippi, to the Documents Control Office of the Chemical Information
   Division of EPA indicated the limited but critical  amounts of  lindane
   used in protecting wood fron beetle attacks.  As the  assessment report
   notes, there are no chemical or ncnchemical alternatives available           *
   for the registered uses of lindane on hardwood logs and lumber.
   Chlorpyrifos is not registered for use on felled hardwood  logs and  .
   lumber and there are no assurances that it will be  effective and  that
   such registrations will be obtained.  It is questionable as to whether
   2 years is sufficient time for registrants to develop and  have reviewed
   by EPA the volume of data needed for a new registration of this type.
   We therefore suggest that EPA give further consideration to the adoption
   of Option 2 (continued registration) with the appropriate  label modifications
   to reduce exposure.

7. Seed Treatment  - We are concerned about the impact of  the proposed
   cancellation of lindane as a seed treatment.  The absence  of an effective
   seed protectant results in insect injury to the seed  with  the  resulting loss
   of plant stand, plant vigor, yield losses, and increased susceptibility to
   disease organisms.  Sane of these losses may necessitate the time and
   expense of replanting which results in yield losses due to the shortened
   growing season.  EPA indicated that lindane seed treatsnents are applied as
   insurance treatments.  Because of the pests involved, this is  the only
   procedure that is practical and applies equally to  the  alternatives.   Most
   crops are planted when soil temperatures are low.   Lindane is  effective and
   stable at these lower soil temperatures while the alternatives generally  are
   not.

   There are no seed treatment alternatives for small grains,  dry peas and
   beans, lentils, sorghum, sunflowers, sugar beets, and vegetables.   In actual
   practice, the small grain producer that uses lindane  seldon treats  his own
   seed, but purchases it already treated.  Lindane is registerd  and effective
   for the control of seed corn beetles, seed corn maggots, and wirewonns.   The
   possible alternatives to lindane on corn are diazinon and  Chlorpyrifos,
   Diazinon is not registered as a seed treatment for wirewonns,  and
   chlorpyrifcs is only registered as a seed treatment for control of  seed corn
   maggot.  Therefore, without lindane, wireworm problems  can be  expected to
   increase to the extent that significant crop losses will occur.   The
   alternatives can only be applied as a planter box treatment to corn.

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   Lindane,  however,  can be applied similarly, as a slurry treatment seed
   dealer or elevator),  and in advance of  planting by automatic seed treatars
   that meter the proper amount of material directly to seeds during the
   planting  process.

   These latter two options, which are essentially closed systems,  should be
   considered as a means of reducing potential exposure, in lieu of
   cancellation.

3. Avccadcs   - We support the delayed "final decision" on this use  until the
   University of Florida has had an opportunity to finalize its data on the
   avccado/mirid project.   Ws believe that sines this  is truly a minor use,  with
   no effective alternative controls available to producers,  every  consideration
   should be given to regulatory options to retain this registration.

'• Ornamental«;  - As  previously stated, 'we agree with  the continued
   registration of lindane on ornanentals (including greenhouse and nursery
   plants) by comerciai applicators.

   Because continuous exposure is not involved and there are  no satisfactory  ,
   subsitutes,  we further recommend that registrations! for lindane  be retained
   for homeowner use  on  ornamentals with appropriate label modifications to
   reduce possible exposure.  This use is only on an "as needed" basis and
   usually requires no more than one application every year or every few
   years.  As pointed cut in the ?D 2/3, l.indane is the only  material
   registered for the control of ali major borer species on woody ornamentals.

10. Curcurbits  -"Lindane is registered for the control of a  wide range of
   insects en cantaloupes, cucumbers, pumpkins, squash, and watermelons.
   This is not true for  any of the alternative insecticides identified
   in ?D 2/3.   The USDA/State/EPA benefits report indicates that significant
   increased treatment costs can be expected from the  cancellation  of
   lindane for these  uses.  Most of the alternative insecticides may be
   more hazardous to  the applicators, beneficial insects,  and pollinators,
   and require more frequent applications.   Therefore,  we suggest the
   selection of Option 2 providing for the continued registered use on
   curcurbits.

11. Minor Uses  - There  are minor use registrations not specifically
   addressed in either the USDA/State/EPA benefits report or  in PD  2/3 that
   are important to regional or local areas and Puerto-Rico.   Of importance
   in the continental United States are preplant treatments labeled for
  . the control of soil insects attacking cedery_,__pjcumbers, kale, lettuce,
   melons, pumpkins,  spinanch, and tomatoes.  Of particular interest
   outside the continental U.S.   are the control of the West  Indian
   sugarcane root borer  weevil and white grubs on sugar cane,  symphylans  (
   and grubs in pineapples, cutworms and white grubs en vegetables,
   foliage applications  for the control of scales, white flies and  other
   foliage insects of mangos, lace bugs en ornamentals, registrations be
   retained  with appropriate label modifications.
                                        t
                                       t
12. Christmas Trees  - The principal insects of concern on Christmas trees
   are the white pine weevil, the pales weevil, and the pine  root weevil.
   The white pine weevil' attacks new terminal growth,  and  this is the



                              v     100

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   only area that requires treatment.  Therefore, insecticidal applications
   can usually be made with ccrnpressed air, handgun, or backpack equipment
   which deliver coarse droplets.  The only registered alternative  for  this
   use, oxydemeton-methyl (Metasystox-R), costs up' to two times that  of
   lindane.  This insecticide is more toxic than lindane, especially  from
   a dermal exposure aspect.

   The pales weevil and pine root collar weevil are attracted to recently cut
   pine stumps where they begin their life cycle in the roots of cut  stumps.
   The most appropriate control for these insects is to make insecticidal
   applications to the cut stumps and adjacent soil.  These treatments  are
   normally applied with conmercially available boon type sprayers, all of
   which deliver coarse sprays.  In the case of the pales weevil, control must
   be obtained to prevent reinfestaticn for the ranaining standing  trees.
   Foliar sprays are seldom used for the control of this weevil if  cut  stumps
   are treated.

   Silvicultural or nonchemical controls including,  basal pruning, duff  removal,
   stump or slash rsnoval, or two year land fallow  have been advocated  but are
   not economically feasible and also increase the  possibility of soil
   erosion.  Losses to pines when only nonchemical  controls are utilized  have *
   been calculated to range fron $644 to 51020 per  acre.  The lower figure
   considers only equipment and labor costs, the higher figure also includes
   yield losses (Scotch pines, Michigan).  In Pennsylvania, lindane is  an
   essential part of their Christmas tree integrated pest management  program.

   Due to the nature of the pests involved and the  effectiveness -of lindane for
   their control, we suggest that Option 2 be selected.  Regulatory options,
   such as protective clothing and equipment modifications, should  be
   considered as alternatives to cancellation.

13. Pecans  - The presently available chemical alternatives for pecan
   phylloxera control, identified in PD 2/3, include oil or malathion.  These
   chemicals are not as effective as lindane; and for six of the major  pecan
   producing States, the use of these products as replacements for  lindane
   would increase control costs by $631,000.  For Georgia alone, control
   costs were estimated to. increase $286,000.  In these same six States,
   yield losses were estimated at $742,000.  We also question the advisability
   of substituting endcsulfan for this use because  of its greater relative
   toxicity.  Lindane is applied once per year so exposure is minimal.
   Further, there are no nonchemical control alternatives.  Until other
   effective environmentally acceptable control measures are assured  for
   those States having this prcblian pest, the availability of lindane is
   essential and should be retained.

14. Forestry  - Although lindane is not widely used in forestry, there  are
   a number of locations where its use is critical  to continued timber
   production.  ?D 2/3 is in error when it states that "a variety of
   chemical alternatives are presently registered"  for forestry uses.
   For the mountain pine beetle, Dendroctpnus pondersae Hopkins, a major
   forest insect pest in many western areas, only three pesticides  are
   registered: lindane, ethylene dibrcmide (EEB), and cacocylic acid.
   Both SDB and cacodylic acid are currently under  Rebuttable Presumption
   Against Registration (RPAR) review and it appears likely that the

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feres cry  uses  of EEB will be cancelled.  Problems associated with the
critical  timing and method of application of cacodylic acid makes use of that
chemical  almost nonexistent.  Further, the  use of trap tress is not possible
in very many situations,  primarily because of the need to treat so many trees
within a  very  limited amount of time.

Ips spp.  and the sprues beetle,  Dendroctcnus_rufipennis (Kirby), are two
other important bark beetles in the West for which lindane and EDS are the
only chemicals reasonably-useful for direct control.

We do not believe chlorpyrifcs, dicrotcphos, and endcsulfan can be considered
alternatives to lindane.   Forest Service research indicates that
chlorpyrifcs is ineffective against the mountain pine beetle.  Dicrotcphos
and chlorpyrifos do not control the spectrun of insects that are controlled  '
with lindane and are more expensive.  Dicrotcphcs and endcsulfan are acutely
toxic and present a real  hazard to applicators far greater than lindane.   In
addition,  endosulfan is limited to use on logs.

Along the Colorado Front  Range and in South Dakota, there are many mountain
areas where private landowners treat bark beetle infested trees with       ,
lindane.   This is not a typical forestry application, but the chemical is
used in a fore-st  environment and cannot be considered an ornamental use.
Although  the Forest Service does not have data on the amount of lindane
being applied  this way, based on the number of citizen inquiries received,
we are sure that a substantial amount of lindane is being used.  Lindane is
the only  chemical available to homeowners for the treatment of bark beetles,
because the fonnulators of the EDB-registered products only sell to State or
Federal agencies.

To reduce losses fron bark beetles on an area-wide basis, a combination of
methods is used.   Various tools are necessary for satisfactory production of
forest products at economical prices,  teiere insect infested timber is
accessible and economically valuable, salvage logging is used to reduce the
insect population and, at the time sane time., recover sane value.
Silvicultural  practices are utilized to provide long-term protection from
bark beetle epidemics. High value trees in recreation areas and around
homes are sprayed to prevent attack.  Nonchemical and silvicultural controls
are useful, but not applicable to all areas and situations.  Direct control
using lindane  or EDB is used on infested trees where  the other methods are
not practical  due to terrain, timber value, or other  factors.  If lindane is
cancelled, one important  tool of this integrated approach is lost.

However,  we agree that one of the major impacts of cancellation will be to
the small private landowners in the South.   Salvage logging of beetle infested
and uninfested green buffer trees is the only effective suppression technique
that can  be used during severe infestations.  The cut-and-Ieave without
chemical  treatment alternative is the one most widely used when salvage is
not practical.   This method is only effective during  the hot summer months
when the  beetles are most active.  Heat is needed to  drive the beetles out
of the infested logs before they have fully developed,  thus stopping the
spread of the  infestation.  However, the best time to  control the beetles is
when they are  in the trees during the colder winter months.  This is when
the cut-and-spray (lindane) treatment must be used.
                                4 X-N «*>
                                i u2

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of the questions of concern about this product is the possible adverse
effect on human health when used inside the hone.  The Weed. Preservative
Assessment Tean has recaimended that PCP not be used in the hate, and sane
labels already carry this statement.  Because the hazards of PC? preclude
its use inside dwellings, it cannot be considered an alternative to
lindane.  Lindane is effective for the control of the wood boring insect
complexes, dry weed tennites, and there are no other safe effective
alternative control measures.  We suggest the adoption of Option 2
(continued registration).  Label modifications are suggested in lieu of
cancellation.
                               103

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             APPENDIX II:
Garments  fran the Science Advisory Panel
                  104

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          FEDERAL INSECTICIDE, FUNGICIDE, AND RODENTTCIDE ACT (FIFRA)

                           SCIENTIFIC ADVISORY PANEL
                 Review of Preliminary Notice of Determination
                 Concluding the Rebuttable Presumption Against
                   Registration (RPAR) of Pesticide Products
                               Containing Lindane
The Federal Insecticide, Fungicide and Rcdenticide Act (FTFRA) Scientific
Advisory Panel has cample ted review of plans by the Environmental Protection
Agency (EPA) for initiation of regulatory action on pesticide products
containing Lindane under the provisions of Section 6(b)(l) of FIFRA as
amended.  The review was completed in open meetings held in Arlington,
Virginia, during the period July 24, 1980, and August 13-14, 1980.

Maximum public participation was encouraged for the review.  Public noticies of
the meetings were published in the Federal Register on July 3, 1980, and July
25, 1980.  In addition, telephone calls and special mailing's were sent to the
general public who had previously expressed an interest in activities of the
Panel.  Written and oral statements-were received from the technical staff of
the Environmental Protection Agency, and from representatives of the Centre
International d1Etudes de Lindane, the National Pest Control Association, the
National Association of Wheat Growers, the Paper Products, Inc., North Dakota
Crops Council, Oregon Wheat Growers League, Washington Wheat Commission, Rachel
Carson Council, Inc., Idaho Wheat Commission, Athena Products Corporation,
University of Idaho, and the North Dakota State Wheat Commission.

In consideration of all matters brought cut during the meeting and careful
review of all documents presented by the Agency and other parties, the Panel
unanimously submits the following report:


   Lindane, the gamma-iscmer of hexachlorocyclohexane, appears to-be the least
hazardous of the widely used organochlorine insecticides.  Available data
suggest that lindane is at worst a weak animal carcinogen, may have a low
degree of fetotoxicity, may disrupt reproductive processes, and can produce
central nervous system excitability after oral and dermal ingestion.  The Panel
agrees with EPA that Lindane is substantially more toxic to young than adults
in both humans and domestic animals and that chronic exposure can sometimes
result in disastrous blood dyscrasias.

   However, for certain uses in insect pest control, e.g. scabies, bark beetles
and powder post beetles, and seed treatment for wireworms, Lindane has no
available substitutes and these and certain very limited applications in
agriculture and protection of ornamentals are both essential and well suited to
Integrated Pest Management procedures.  Furthermore, the total amounts of
Lindane used for these uses, e.g. < one million pounds annually, represent a
minimal hazard to the environment.
                                   105

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Therefore,  the Panel  has the fclicwing Garments and reccrnmendaticns:

1.  Household uses  of Lindane in treated shelf paper and floor waxes  provide
    an unwarranted  risk to the householder and should be cancelled
    immediately.

2.  Pet uses for unrestricted use as flea collars,  dog dusts,  and dog
    shampoos should be cancelled immediately.   Veterinary medical
    preparations of Lindane for use in mange and scabies and for flea,  louse
    and tick control  should be available as collars, powders,  sprays,
    shampoos, and dips under restricted classifications for use by licensed
    veterinarians only with label cautions and requirement for protective
    clothes, as proposed by EPA.

3.  Ornamental applications for unrestricted use by the homeowner should be
    cancelled immediately.   Ornamental uses restricted to commercial
    operators should  be continued with' full warning label cautions about the
    hazards of cancer, fetotoxicity, and central nervous system effects and
    a caution that  wcmen of child-bearing age and children must avoid
    exposure.  Full protective clothing must be worn.

4.  Lindane registrations for powder post beetle control should be continued
    under restricted  classification for use by registered Pest Control
    Operators with  full warning label cautions and  full protective clothing
    proposed by EPA.

3.  Livestock applications should be placed under restricted classification
    for use by certified applicators only with full warning label cautions
    and mandatory protective clothing as proposed by EPA.

6.  Uses on pineapples should be retained with warning label cautions
    proposed by EPA.

7.  Uses on cucurbits should be continued under restricted classification
    with full warning label and mandatory protective clothing  proposed  by
    EPA.

8.  Uses on avocadces should be continued under restrictive classification
    with full warning label and mandatory protective clothing  proposed  by
    EPA.

9.  Uses on pecans  should be continued under restricted classification  with
    full warning label and mandatory protective clothing proposed by  EPA.
\
10. Uses on Christmas trees should be continued under restricted
    classification  with full warning label and mandatory protective clothing
    proposed by EPA.

11. Uses in forestry  for bark beetle control should be continued under
    restricted classification for application by certified operators  with
    full warning labels and mandatory protective clothing as proposed by EPA.

12. Applications to hardwood legs and lumber should be continued under
    restricted classification with full warning labels and mandatory


                                1  n t
                                J  \j u

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       protective clothing as proposed by EPA.  Special caution should be given
       to improving 'work place practices and disposal of treated sawdust and
       shavings.

   13. Seed treatment uses of lindane should be continued under restricted
       classification by certified applicators with full warning labels and
       mandatory protective clothing proposed by EPA.  Testimony presented to
       the Panel suggests that 90% of Lindane seed treatments are made with
       closed mechanical systems that essentially eliminate operator exposure.
       EPA should sponsor an educational program to make use of such closed
       mechanical seed treatment systems universal.

   14. The suspicion that Lindane interferes with reproductive processes
       (hormones) indicates that a 3-generation reproductive study should be
       performed on an appropriate laboratory animal.


FDR THE CHAIRMAN:

Certified as an accurate Report of Findings:
               !                               I
H. Wade Fowler, Jr., Ph.D.
Executive Secretary
FIFRA Scientific Advisory Panel

CATS:  October 6, 1980
                                  107

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  APPENDIX III:
EXPOSURE ANALYSIS
     1 •"» O
     I U O

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INTPCCUCTICN


This appendix describes, for each use of lindane:

0 the exposure assumptions and estimates made in PD 2/3,
  conments received by EPA about those assumptions, and
  EPA's final assumptions regarding exposure associated with that use.
Please refer to Table 3   for a ccrnpariscn of PD 2/3 and PD 4
exposure estimates.

Readers who are interested in seeing the mathematical steps used to
derive exposure estimates from these assumptions may request a copy of the
"Lindane PD 4 Exposure Tables".  These are available from the Lindane
Project Manager, Office of Pesticide Programs, U.S. EPA, 401 M St, S.W.,
Washington, D»,C., 20460.          !
                                   109

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I. ASOVE-5HCULDER SPRAYS  - AIR BLAST AND POWER HAND GUN

   A. Ornamentals -  Comtercial Applicators

      1. The Agency's  Exposure Calculations  in PD  2/3

The Agency  assumed that dermal and respiratory exposure to applicators during
lincane  treatment of ornanentals cculd be estimated using the model of Wolfe et
al. (1974)  as determined  during hand-pressure spraying of fenthion for mosquito
control.  A 0.5%  w/w lindane solution was assumed.  It was also assumed that a
commercial  applicator  worked 3-8 hours a day for 1-15 days per year.  The
cohort at risk  for conmerical applications was estimated to be from 30-1200.

      2. Garments on the  Agency's ED 2/3 Calculations

Edwards  (comment  £94)  agreed with the Agency's choice of Wolfe et al. (1974) as
a nodel  for estimating exposure during application of lindane to ornanentals.
In this  study,  exposure estimates were made  during mosquito control operations
using hand  pressure  sprayers.  However, Edwards used an approximate mean cohort-*
at-risk  figure  of 600  people in place of the 30-1200 range used in FD 2/3.
Edwards  also suggested that 0.06% is a more  reasonable use dilution, based on
USDA recommendations.

Both Nielsen (1982)  from  the Ohio Agricultural and Research Center, and Felix
(1982) frcra the National  Arborist Association, agreed that a cotroercial
applicator  would  be  exposed to much larger volumes of lindane spray than a
hcroecwner would.   Protective clothing is currently wornr however.  They also
believed a  more reasonable estimate of exposure duration for corroercial
applicators would be eight hours a year.

      3. The Agency's  ED  4 Response

The following protective  clothing measures are assumed in the ?D 4 exposure
analysis: a long-sleeved  shirt, long pants,  shielded hard hat, and impermeable
gloves.  It is  assumed that this protective  clothing reduces dermal exposure
by at least 80%.   In seme cases, rubber raincoats  and respirators are also
worn.

Based on reevaluation  of  label data, the Agency agrees that a 0.06% final use
concentration is  a more reasonable estimate  than 0.5%.  The Agency also agrees
that a mean value of 600  persons at risk is  a reasonable estimate to use.

For estimating  exposure to counercial applicators, the Agency uses a model
which measured  exposures  during power hand gun spraying of fruit orchards fron
a portable  machine using  dieldrin.   Exposure duration is assumed to be eight
hours per year  for comercial applicators.*
                                    110

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    3.  Avocados

        1.  The Agency's Exposure Calculations  in ED 2/3

The Agency assumed that spraying operations for avocados were identical to
those for other fruit orchards, and that applicator exposure could be estimated
using the models in Wolfe et al., 1967. Based on the Wolfe study, dermal and
respiratory exposures were 50 and 0.1 mg/hr respectively.  A single pest
control operator was assumed to treat one average avocado farm in one 8-
hcur day, twice a year.

        2.  Garments on the Agency's PD 2/3 Calculations

Edwards, representing CIEL (comment $94), did not disagree with the use of the
exposure data contained in Wolfe et al. (1974).  However, he recommended using
more appropriate exposure values for 0.05% sprays, i.e. 22.5 mg/hr for dermal
and 0.035 mg/hr for respiratory exposures.

        3..  The Agency's ED 4 Response                                          ,
                                                     i
The Agency has evidence (Day, 1982) that protective clothing is not currently
being worn by most applicators during spray operations with air blast •
equipment.  If protective clothing measures (such as a long-sleeved shirt, long
pants, impenteable gloves, wide-brimmed hat or  a roof-type shelter on the
machinery employed) were worn, it is estimated  that dermal exposure would be
reduced by about 80%. .

The Agency reevaluatated the data in the Wolfe  et al. (1967) paper, and
calculated new expected values of 20 mg/hr and  0.04 mg/hr for dermal and
respiratory exposures,  respectively.  However,  studies show dermal exposure
varies considerably during air blast spraying,  generally within the range of 2-
50 mg/hr with 40 mg/hr being the most frequent  (Day, 1982).  Therefore,
the Agency has used 20  mg/hr and 0.04 mg/hr for dermal and respiratory
exposure, respectively, to estimate exposure during air blast spraying of
avocados.

    C.  Pecans

        1.  The Agency's Exposure Calcalations  in PD 2/3

The Agency assumed that exposure to applicators applying lindane (0.05% w/w) to
pecan orchards was conparable to applicator exposure during spraying of other
fruit orchard crops, i.e., 50 mg/hr and 0.1 mg/hr for .dermal and respiratory
exposures, respectively (Wolfe et al., 1974).   No protective clothing was
assumed.   A single pest control operator was assumed to treat one average pecan
farm in one day, once a year.

        2.  Comments on the Agency's PD 2/3 Calculations

Edwards (comment 294) suggested that more reasonable values from the Wolfe et
al. (1974) paper should be used by the Agency.  He suggested that for a 0.05%
spray, 22.5 mg/hr was more appropriate than 50 mg/hr for estimating dermal
exposure, and that 0.035 mg/hr was more reasonable than 0.1 mg/hr for
estimating respiratory exposure.


                                   11 1    *

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         3.   The Agency's FD 4 Pespor.se

The Agency  has evidence (Day, 1982)  that protective clothing is  not  currently
being  worn  by most applicators during spray operations  with  air  blast
equipment.   If protective clothing measures (such as a  long—sleeved  shirt,  long
panes,  impermeable gloves, wide-brimmed hat, or a roof-type  shelter  on  the
machinery employed)  wera worn,  dermal exposure would be  reduced by  an
estimated 80%.

Dermal  exposure during air blast spraying generally varies from  2-50 mg/hr
(Day,  1982)  with 20  mg/hr being the most frequent.   Therefore, the Agency has
used the estimate of 20 mg/hr, to estimate exposure during air blast
spraying of pecans.

    D.   Livestock

         1.   The Agency's Exposure Calculations in FO 2/3
                                           i                                     <
The Agency  assumed that an applicator's exposure in dipping  operations was
negligible  in comparison to spray operations.   It was also assumed that an
applicator's exposure to lindane (0.045% w/w)  during spray operations was
comparable  to exposure during mosquito control operations (Wolfe et  al., 1974)
using a fenthion (0.06% w/w)  spray-.  No protective  clothing  was  assumed.  The

cohorts at  risk were estimated to be 248,000 persons, and an applicator was
estimated to be exposed 2.1 - 2.4 hours a year,

         2.   Comments on the Agency's FD 2/3  Calculations

Edwards (comment #94)  agreed with the Agency's assumption that dipping of
livestock is rare compared to spraying.  He  also agreed with the Agency's
choice  of surrogate  models.  Edwards presented evidence that applicators
usually wear protective clothing and respirators.

         3.   The Agency's FD 4 Response

Sufficient  evidence  was submitted to the Agency that protective  clothing is
currently being worn by commercial applicators spraying lindane  en livestock.
The following protective clothing measures are assumed  in the FD 4 exposure
analysis: a  long-sleeved shirt, long pants,  aprons, boots, respirators, and
impermeable  gloves.   It is assumed that this protective clothing reduces dermal
exposure by  at  least 80% and respiratory exposure by at least 90%.

The Agency reevaluated use patterns  for spraying livestock with  lindane, and
in the  FD 4  exposure analysis,  uses  another  model which more accurately
reflects the exposure potential than that model used in the  FD 2/3 analysis.
The Agency uses exposures fron the spraying  of dieldrin to fruit orchards
with a  power hand-gun from a portable machine  using a dieldrin spray.
                                   1  12

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II.  ABOVE-SHOULDER SPRAg; BACKPACK OR HAND PRESSURE EQUIPMENT

    A.  Ornamentals - homeowner applicators

        1.  The Agency*s Exposure Calculations in FD 2/3

The Agency assumed that dermal and respiratory exposure during" lindane
treatment of omanentals could be estimated using the model of Wblfe et al.
(1974) as determined during hand-pressure spraying of fenthion for mosquito
control.  A 0.5% w/w lindane solution was assumed.  It was also assumed that
homeowner would spray only one hour/year.  The cohort at risk for homeowners
was estimated at 75,000.

        2.  Garments on the Agency's PD 2/3 Calculations

Edwards (comment #94) agreed with the Agency's choice of Wblfe et al. (1974) as
a model, but suggested that 0.06% is a more reasonable use dilution, based on
USDA recommendations.
                                                                        i
Both Nielsen (1982) from the Ohio Agricultural and Research Center, and Felix
(1982) from the National Arborist Association, agreed that for estimating
homeowner exposure while spraying ornamentals, the  mosquito control model was
reasonable for the Agency to use.  However, they both agreed that homeowner
applicators would be exposed to mueh lower volumes of lindane spray than
cauuercial applicators.  For homeowners, the PD 2/3 value of one hour per year
was considered reasonable.

        3.  The Agency's PD 4 Response

The Agency assunes that protective clothing is not currently worn by homeowners
applying lindane to ornamentals, and that there is exposure duration of one
hour per year.  Based on reevaluaticn of label data, the Agency agrees that a
0.06% final use concentration is a more reasonable estimate than 0.5%.  As
recommended by Nielsen and Felix, the mosquito control model is retained for
estimating homeowner exposure.

    3.  Forestry

        1.  The Agency's Exposure Calculations in PD 2/3

The Agency assumed that applicator exposure to lindane (0.5% w/w) using back-
pack sprayers during forestry operations was comparable to applicator' exposure
using hand-pressure sprayed fenthion (0.06% w/w)  solutions for mosquito
control.  Applicators were estimated to treat 32 trees/day, 5 minutes/tree, 30
days/year.

        2.  Comments on the Agency's PD 2/3 Calculations

Edwards (cement 394) agreed with the Agency's use of a back-pack sprayer as
representative equipment in forestry operations,  with a 0.5% lindane
concentration, and with the Agency's choice of a surrograte model, i.e.  Wolfe
et al., 1974.

Edwards pointed out that an error occurred in the PD 2/3, where it was stated •

                            -113

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chat one  applicator treats 32 trees/day.   According to Edwards,  the Agency's
backup document  for the FD 2/3 Exposure Analysis (SEA, 1980b) had  two
applicators  treating 32 trees/day.

Laut (1982)  fron the Colorado State Forest Service, and Johnson  (1982) fron the
USDA Forest  Service in Colorado,  said  that protective  clothing measures
actually  worn  include gloves, long  pants,  long-sleeved shirt, boots (often) and
a hard hat  (often).   Both agreed  that  the  other assumptions were reasonable.

        3.   The  Agency's PD 4 Response

The following  protective clothing measures are  assumed in the PD 4 exposure
analysis: a  long-sleeved shirt, long pants,  and impermeable gloves.  It is
assumed that this protective clothing  reduces dental exposure by at least 80%.

A study more appropriate than the Wolfe et al.  (1974)  study for estimating
exposure  to  forestry personnel has  been published  in the literature and used in
the PD 4.  Lavy  et  al.  (1980) estimated exposure levels to forestry personnel
who apply 1.9% w/w  2,4,5-T by back-pack sprayers to be 26.7 mg/hr and 0.027    ,
rog/hr for dermal and respiratory  exposures,  respectively.

The Agency agrees that an error was made in translating the information from
the PD 2/3 revised  exposure analysis to the actual PD  2/3.  The text of the PD
2/3 should have  read that two applicators  treated  32 trees per day (40 hours
per year  per applicator).          ~~


III.  CRAWL  SEACE TREATMENTS
    Structures

        1.  The Agency's  Exposure Calculation with PD 2/3

For evaluating lindane  exposure to  applicators during crawl space treatment for
powder post beetles,  the  Agency used  a model based on Batchelor and Walker
(1954), where a 0.05% parathion solution was hand sprayed in fruit orchards.  A
spraying time of one  hour per day,  10-20 days per year was assumed.  The cohort
at risk was estimated to  be  500-1000  persons.  A 0.5% w/w lindane solution was
assumed.  It was assumed  that no protective clothing was worn.

For evaluating lindane  exposure to  residents after powder post beetle
treatment, the Agency used data from  the United states Public Health Service
(USFHS) Communicable Disease Center (PHS/CDC, 1952).  In this study, lindane
was deposited on surfaces at a rate of 25 mg/ft2, and then room air
samples were taken at intervals for 8 days.  An 85-day weighted average
of 0.05 ug/1 (or 0.05 mg/m^)  was used.  Occupants were assumed exposed
for 24 hours a day, 84  days  a year, and it was assumed that 10,000 homes
were treated annually.

        2.  Comments on the  Agency's  PD 2/3 Calculations

Edwards (comment $94) disagreed with  the Agency's choice of models for
evaluating exposure to  home  occupants after lindane treatment for powder post
beetles.  According to  Edwards, EPA had little justification for the assumption


                              :     114

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that surfaces with lindane deposits of 25 mg/ft2 were saturated with lindane.
Much of the lindane would be adsorbed tightly on the wood, particularly  if the
wood were dry, so that the lindane would not be available for vaporization.
Also, the study refers to lindane concentrations in a closed room, where air
concentrations would be higher than in a ventilated rocra.  According to Edwards,
Queen (1953) showed that most of the lindane contaminating the surface of a
building  at a rate of 5.2 ug/in2 (0.75 mg/ft.2)  disappeared within 6 days.

Concerning ventilation rates, Edwards criticized the Agency for not including
an air exchange rate of 3 per hour, which had been used for other uses in the
?D 2/3.  As for the EPA assumption that the whole basement area would be
treated, Edwards pointed cut that lindane is usually limited to spot treatments.
Of all the assumptions made by EEA, Edwards most strongly disagreed with the
assumption that an infested hone would be treated every year.  Edwards felt a
more reasonable estimate for an infested home would be treatment every 10
years.

As for evaluating exposure to applicators, Edwards agreed with the Agency's use
of Batchelor and Walker (1954), although he believed the exercise was academic,,
because treatments are usually done by professional applicators who would be
wearing protective clothing.

Concerning the Agency's estimate of cohort at risk (500-1000 persons), the
National Pest Control Association (comment #5B) estimated that over 4,000
applicators are involved in application of lindane for control of wood-
destroying pests.

A more appropriate model for estimating exposure was brought to the Agency's
attention (via personal communication, not as an official rebuttal comment) by
Carr, from the National Pest Control Association.  He pointed out a study by
Maddy et al. (California Department of Food and Agriculture, 1979) which
estimated applicator and hone occupant exposures to chlordane during crawl
space treatment.

        3.  The Agency's PD 4 Response

Sufficient evidence was submitted to the Agency (Edwards, fron CIEL; Carr, from
the NPCA; Williams, from the USDA Forest Service, Southern Forest Experiment
Station) that protective clothing is currently being worn by applicators
spraying structures with lindane.  These protective clothing measures include a
Icng-sleeved shirt, long pants, impermeable gloves, and a cartridge respirator.

Based on extensive telephone conversations with Williams (USDA Forest Service,
Southern Forest Experiment Station, Gulfport, MI) and Carr (NPCA), the Agency
has fine-tuned the time estimates for applicator exposure, assuming now that an
average crawl space takes three hours to treat, and that an average applicator
dees 5 lindane crawl space treatments per year.

For estimating exposure to residents after lindane crawl space treatment, the
Maddy et al. (1979) study is used.   Living area air was monitored for chlordane
residues at intervals up to 30 days (at which time no chlordane residues were
detected) after application.   It is assumed that lindane air levels will be no
greater than these chlordane levels for crawl space treatment where 0.5% w/w
lindane is used, compared with 1% w/w chlordane.  It is assumed that respiratory

                            :     115

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exposure  could  occur to residents for up to 30 days,  ones every 10
years.

IV.
    A.  Hardwood  Iocs and lumber

        1.  The Agency's Exposure Calculations in ED 2/3

Because no  actual exposure data were available,  the Agency made  the  following
assumptions to estimate applicator dermal exposure: no protective  clothing was
worn; -the exposed skin area included head, neck, "V  of  chest,  hands, and
forearms; operators  were exposed to a cunulative dose equivalent to  a single
wetting of  all exposed skin;  a 0.5% w/w solution of lindane  was  used; 7 ml of
aqueous solution  wets an average pair of hands (0.082 n»2)  up to  the  wrist; an
applicator  would  be  exposed 8 hours a day, 5  days a week,  50 weeks a year.

To estimate respiratory exposure, the Agency  assuned the  following:  all surface
areas around  the  dip vat were saturated with  lindane; a saturation vapor       ,
concentration of  lindane at 20°C of 0.5 ug/1;  10% of lindane saturation
represents  the best  estimate of air concentration;  an adult  male breathing
rate of 1.8 m3/hr.

        2.  Comments on the Agency's PD 2/3 Calculations

Edwards, representing the Centre International d1 Etudes du Lindane (CIEL,
ccnroent 194),  submitted information showing that about 35% of  lunber is treated
by the green  chain dip vat method, and 65% by the lunber package dip vat
method,  in the latter procedure, the packages are  handled by  fork lift trucks
and are not touched  by the workers.   A 0.056%  treatment solution is  used, made
frcm 1 pint of 11% w/w lindane in 20 gallons  of  water.  Edwards  estimates that
work gloves are universally worn, and that hard  hats are worn  in more than 90%
of the mills.

As a model  for estimating respiratory exposure near a dip  vat, Edwards
suggested using a study (FHS, 1952)  in which  the walls of  a  closed room were
saturated with lindane,  giving an average lindane concentration  in the air of
0.208 ug/1.

Concerning  the number of hours worked handling treated lumber, Edwards
estimated,  based  on  several inquiries to the  hardwood industry,  that a 4-hour
exposure per  day, a  5-day working week,  and a 40-week exposure per year would
be -.more reasonable estimates  to use.

DSDA carroented (see  Appendix 1)  that appropriate label modifications to reduce
exposure should be considered.   The protective clothing USDA recommended were
long-sleeved  shirts,  pants,  impervious gloves, and  boots.  USDA  also
reconroended that  impervious aprons should be  required in areas where normal
treatment practices  could probably lead to splashing of the  treatment solution
and where aprons  do  not constitute a hazard around  equipment.

Zoecon Corporation (1981)  submitted a study to the  Agency  in which lindane air
concentrations were  measured  at various  locations  in a southern  hardwood mill
during borer  treatment with lindane.   Evidence was  also submitted  by Zcecon


                              " _ .  116

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chat protective clothing is routinely worn in hardwood mills.

        3.  The Agency's PD 4 Response

Sufficient evidence was submitted to the Agency by CIEL representatives  that
protective clothing is currently being worn in the hardwood  industry.  These
protective clothing measures include a long-sleeved shirt, long pants, rubber
apron, impermeable gloves, and a hard hat.  Although dermal  exposure  is
possible, it is assumed to be negligible when this protective clothing is worn.

Based on a study conducted for Zcecon (1981) in a southern hardwood mill during
borer- treatment with lindane, the average lindane air concentration is
assumed to be 0.0059 mg/m3.

The Agency accepts the Zoecon estimate that an 8-hcur daily  exposure, a  5-day
working week, and a 40-week exposure per year are reasonable conservative work
estimates to use.

    B.  Dog Dips

        1.  The Agency's Exposure Calculations in H3 2/3

Because no actual data" were available, the Agency made* the following
assumptions to estimate exposure to veterinarians using lindane dog dips: a
veterinarian exposed both hands to~a dilute product 5 minutes a day,  26  times a
year; the final concentration of lindane was 0.085 g/ml; 7 ml of solution "just
wet" hands; no respiratory exposure occurred; and no protective clothing was
assuned.  For estimating the exposure to dog owners after their pets  have been
treated with lindane, the Agency assumed the following:  lindane volatilized
frcm the hair of the animal, and this volatilized lindane was 100% respirable;
the Agency did not feel it was possible to quantify dermal exposure which
occurs after dipping; the animal has access to 12,000 ft3; use of lindane was
0.236 mg/ral of final solution for post-dip exposure; after towel drying,
79 ml of wash solution was retained by a small dog, 237 ml by a large
dog; exposure after a dog was dipped lasted for 72 hrs,  once a year;  a
dilution factor of 10 was-assumed for air exchange; and the  breathing
rate was 1.2 ra3/hr.

        2.  Garments en the Agency's ED 2/3 Calculations

Edwards (Garment =£94) argued that SPA's assumption of 7 ml wetting the hands
was unrealistic.  2.5 ml was more likely, based on simple laboratory
experiments performed by Edwards.

For estimating respiratory exposure, Edwards recamended using the data  from
Queen (1953), which showed that 1 gram vaporizing into a 1300 ft3 room
for 24 hours gave a concentration of 0.4 ug/1 of lindane in  air.  A 50%
lung absorption factor was used, as was the-estimate that a  dog spends
16 hours/day in the house.

        3.  The Agency's H3 4 Response

Insufficient-evidence was submitted to the Agency that protective clothing is
currently being worn by veterinarians dipping dogs with lindane.  If  the

                             -'117

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following  protective clothing measures were worn (a long—sleeved  shirt,  long
pants, and impermeable gloves), it is estimated that dermal  exposure  would be
reduced by 80%.

The Agency agrees  with Edwards that the PD 2/3  model was too hypothetical, and
contained  a significant math error (5 rain/60 rain which should have  been  60
min/5 rain).  However,  the Agency does not have  an obvious  suroggate study to
use as an  appropriate model.   Therefore,  the Agency assunes  that  dermal
exposure while dipping dogs is no greater than  the dermal  exposure  of 3.6 mg/hr
during mosquito  control operations, using 0.06% fenthion sprays (Wolfe et al,
1974).  As in the  PD 2/3, veterinarians are assumed to be  exposed 5
minutes/day, 26  days/year.

For estimating post-treatment exposure to dog owners or hone occupants after
iindane treatment,  a different model is used in the PD 4 because, as  with the
veterinarian exposure,  the FD 2/3 model was too hypothetical.  Therefore, the
Agency assumes that lindane indoor air concentrations are  no greater  than 0.002
mg/nP, which is  based on average lindane air concentrations  in a  closed
room where a lindane mothproofing product was being used inside a wardrobe
(Haag and  Prugmayer, 1981).  Because this value represents an actual
lindane air concentration in a roan without normal ventilation, an  additional
air exchange rate  of 3 exchanges per hour is figured into  the Agency's
calculations.

The following additional assumptions are made in the PD 4: there  will be
potential  respiratory exposure for three days after the dog  is dipped, once a
year; there is 100* lung absorption because lindane is in  the vapor state;
residents  spend  an average of 15 hours per day  indoors;  these residents  have an
average breathing  rate of 0.64 nP/hr.  (For an  explanation of the last
two assuitpticns, please refer to SHELF PAPER, EPA's PD 4 Response).

    C.  Dog ShcSiipoos

        1.   The Agency's Exposure Calculations  in PD 2/3

Because no actual  exposure data were available, the Agency made the following
assumptions to estimate applicator exposure: the concentrate came  in direct
contact with the shanpcoer's  hands;  per washing,  a total volume of  15 ml of
soap came  in contact with the hands;  contact time with the concentrate was 3
seconds, with the  diluted soap was 5  minutes per dogwash;  7  mis "just wet"
hands; there was negligible respiratory exposure curing shanpcoing; and  lindane
transferred to the  oily layer of a dog's pelt.   -

For estimating post-treatment exposure to pet owners and residents, the  Agency
assumed that 15 ml of a 0.5%  lindane formulation was retained by  a  small dog,
45 ml by a large dog;  the treated animal had access to a 12,000 ft^ area; the
resident had a 1.2  m^/hr breathing rate;  lindane volatilized for  72
hours after treatment;  there were 26  treatments per year;  100% of the
lindane was respired.

        2.   Comments on the Agency's PD 2/3 Calculations

Edwards, representing CISL (comment £94), criticized the Agency's assumption of
3 seconds  contact  with the concentrated solution before scan reaches'  the hands
                                   116

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as "an extremely complex and inapplicable calculation".  In his calculations,
Edwards used one ml, presumably as the amount that will cover a pair of  hands.
Edwards did not recamend changing the other assumptions in estimating dermal
exposure.

For estimating pest-treatment lindane respiratory exposure to pet owners and
residents, Edwards suggested slight modifications of EPA's model: that there
would be 10 air changes per hour, that a resident would spend 16, not 24 hours
a day indoors, and that 50% of the vapors would be respirable.

        3.  The Agency's PD 4 Response

The Agency assumes that short-sleeved shirts and long pants (but not gloves)
are worn by pet owners while shampooing their dogs.  The exposed areas get
completely wet with the lindane shampoo solution.  Based on a laboratory
study evaluating water retention on hands (Weaver, 1977), the Agency
assumed that 0.01 ml of water/shampoo solution covers one on^ of exposed
skin area, during one shampoo application.  Pet owners are assumed to wash
their dogs once per year.

For estimating post-treatment respiratory exposure to residents and
applicators, the same assumptions were used for the dog shampoo use as for  the
dog dip use (Please refer to Dog Dip - The Agency's PD 4 Response).


V.  ENCLOSED AREA SPPAYS '

    A.  Industrial use moth sprays

        1.  The Agency's Exposure Calculations in PD 2/3

Because no actual exposure data were available, the Agency made the following
assumptions to estimate exposure during application of industrial lindane moth
sprays: no dermal exposure; an aerosol of 0.1% lindane produced 50% particles
of 10 microns or less, and 50% between 10 and 40 microns; 90% of the spray
impinged on clothing;  clothes were treated in a well-ventilated area for 2
minutes; lindane concentrations in the vicinity of the spray and at the  time of
spraying were similar to those of 30% freon 12 formulation, which was 44.25 ppm
in the breathing zone; spraying was repeated 26 times per year.

To estimate respiratory exposure to occupants after lindane treatment, the
Agency assumed the following: 28 grams of 0.1% spray were used every 2 weeks,
year-round; vapori2ation was continuous over a 2 week period, at which time all
the lindane would be vaporized; volute of the work space was 6000 ft3; the
air exchange rate was 3 per hour; exposure was 10 hours/day, 365 days/year;
vapors were 100% respirable.

        2.  Ccmments on the Agency's PD 2/3 Calculations

Edwards, representing CISL (comment *94), disagreed that an aerosol has  a
particle range frcm 1-40 microns.  He also said an air turnover rate of  1 per
hour seemed low.  However,  Edwards did not disagree with the Agency's choice of
models.


                            i  " 119

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For  estimating occupant exposure to industrial moth sprays,  Edwards  agreed with
the  Agency's  model,  except he thought it would be better to  assume that
volatilization is complete after one week (not two)  and that 50%  (not  100%) of
the  particles would  be of respirable size.

         3.  The Agency's H3 4 Response

A recent study was submitted to the Agency by the Jenick Corporation,  which
measured dermal .(0.41 rag/ruin) and respiratory (2.3 ing/fa3)  exposures  to
home applicators using resmethrin formulated in a pressurized container.
In the Agency's opinion, this is a reasonable model for estimating applicator
exposure to lindane  during the spraying of  commercial establishments.

Consistent with the  assumptions made for the household and pet uses  of lindane,
it is assumed that there is potential for building occupant  exposure for a
three day period, at which time all the iindane will be vaporized.   All of the
vaporized lindane is assumed respirable.

Other assumptions include the following:  building occupants  spend an average of
8 hours/day,  225  days/year in the exposed area (but since the lindane  is       *
completely vaporized after three days,  the  actual assumed exposure is  78
days/year); there are 3 air changes per hour;  an average breathing rate for
light -work is 1.2 m3/hr.

     B.   Funigation devices        ~~

         1.  The Agency's Exposure Calculations in ED 2/3

Based on a study of  lindane air concentrations following fumigation  (WARF
Institute, Inc.,  1970), the Agency estimated average concentrations  of 0.014
ug/1 on  a year-round basis, assuming 26 applications a year.   It was also
assumed  that  a person spent 24 hours/day indoors,  365 days/year, and that the
vaporized lindane was 100% respirable.

         2.  Carments on the Agency's PD 2/3  Calculations

Edwards,  representing CIEL (cuutient #94), disagreed that treatments  would be
done every two weeks in homes with no ventilation.   Based on the data  in Queen
(1953),  Edwards estimated that lindane treatments would not  exceed twice a
year, that lindane residues would disappear within 7 days, that there  would be
an air exchange rate of 3 per hour, that a  resident would spend no more than 16
hours a  day indoors,  and that 50% of the vaporized iindane would be  absorbed by
the  lungs.

         3.  The Agency's PD 4 Response

The  Agency has reconsidered the exposure that  results fron the indoor  use
of smoke fumigation  devices.  The Agency's  calculations are  based on the actual
ancient  air residue  data reported for 21  days  by the WARF  Institute, Inc.
(1970).   The  Agency  assumes all exposure  to be respiratory,  that a person
spends an average of 15 hours per day indoors, and an average  breathing rate
of 0.64 rn^/hr.  The  Agency did not factor any  air exchange rate within the
house since the air  residues are actual measurements.


                             :"     120

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The Agency assumed that' the smoke fumigation device would be used twice
per year.

    C.  Uninhabited building sprays / empty storage bin sprays

        1.  The Agency's Exposure Calculations in PD 2/3

Because no actual exposure data were available, the Agency made the following
assumptions to estimate applicator exposure: a 2.2% w/w lindane aerosol
solution was used for two minutes, 12 tines a year; lindane air concentrations
were comparable to spraying of 30% freon solution (44.25 ppm) for 2 minutes
(Gay et al., 1975); the breathing rate for light work was 1.2 ra^/hr; 1
ppm of lindane in air = 0.0119 mg/1; there was no dermal exposure.

        2.  Comments on the Agency's FD 2/3 Calculations

Edwards, representing CIEL (comment £94), suggested that the Agency use the
data given by Culver et al. (1956) for 5% aerosol application of malathion and*
chlorthion during mosquito control operations, i.e. an estimated respiratory
exposure of 0.28 mg/hr.  He assumed 50% of the particles are respirable, and a
use dilution of 0.05%-lindane.

        3.  The Agency's FD 4 Response

Because the use patterns are so similar, exposures to applicators while
spraying aerosol formulations in uninhabited buildings and empty storage bins
are considered together.

The Agency agrees with Edwards that it would be more reasonable to use an
actual aerosol study rather than the freon model.  Therefore, the Agency uses
the suggested Culver et al. (1956) model, which measures dermal values of 6.6
mg/hr and respiratory values of 0.3 mg/hr for 5% sprays.  All (100%) of the
particles are assumed of respirable size because of the aerosol formulation.

Insufficient evidence was submitted to the Agency that protective clothing is
currently being worn by applicators spraying lindane for these uses.  If
protective clothing measures were worn (a long-sleeved shirt, long pants, and
impermeable gloves), it is estimated that dermal exposure would be reduced by
80%.

VI.  DUSTS

     A.  Seed treatment

         1.  The Agency's Exposure Calculations in PD 2/3

For estimating dermal exposure, the Agency assumed the following: all lindane-
treated seed was by the manual planter box method, using a 25% w/w lindane dust
formulation; the applicator wore no protective clothing; one gran of dust
formulation can completely cover hands; 20% of the dust formulation reaches the
exposed skin.  For estimating respiratory exposure, the Agency used a model



                           --•"'121"

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based on  exposure to cotton dust (US/HEW, 1974).   The Agency assumed that
average lindane air concentrations around the planter box = 10 mg/rn^,
that an operator spends approximately 60 minutes per day mixing  seed,
and that  there  was 100% respiration of the lindane dust.

          2.   Garments on the .Agency's PD 2/3 Calculations

Zoecon Corporation (comment $94}  presented the Agency with the details  of a
field experiment conducted in 1980 which attempted to determine  the
concentration of lindane in the air during the various operations  involved with
the "mechanized planter box" method of treating wheat and barley seed.   In
order, to  estimate "worst-case" exposure, air saiples were purposefully  taken
downwind  in  the dust plume.   During the treatment operations, filling of
equipment, and  transfer of treated grain, lindane air levels of  0.7 - 3.6
mg/m^ were present in the plume.   During the actual seeding,  using  either
open or closed  cab tractors, the potential for lindane exposure  was
estimated to be from 0.001 - 0.02 rag/m3.

Concerning the  Agency's choice of the manual planter box method, versus the
mechanized planter box method or seed treated commercially in bulk,  Zoecbn did*
not disagree with this choice, stating that with  each of the two
treatment methods there was  dust generated during the movement of seed
(commercial)  or during the augering process (mechanized).  Zoecon agreed that
commercially treated seed and auger treated seed  produce seme (albeit less)
lindane dust exposure.            -

Zoecon submitted a detailed  table of typical seed treatment parameters,  for
both large and  small seed types.   This table included such parameters as time
to seed an acre,  seeding speed (acres/hour), time to refill hoppers, total time
treating  seed,  and acres treated in 10 hours.  Using the data from  this table,
Zoecon estimated that seed treatment would take 12 minutes per 10-hour  day, two
days a year,  and that actual seeding would require 10 hours/day, two days/year.

Concerning the  particle size distribution of lindane dust which  can be  respired
by an applicator,  Zcecon presented evidence (calculated by coulter  counter
methodology)  that 50% by weight of the material is nonrespirable because
particles are greater than 30 u in size.  Therefore,  according to Zoecon,  a
measured  air concentration of lindane in a typical dust should be corrected by
at least  a factor of 50% by  weight for nonrespirable particles.  The remaining
50% constitutes exposure,  but only 10% of that is by the more significant
inhalation route,  the other  90% being best compared to an oral administration.

Concerning protective clothing measures, Zcecon stated that cool weather
conditions prevalent during  the planting season increase the  likelihood  that
protective clothing (long—sleeved workshirt, long pants,  impermeable g.loves)
would be  worn to reduce dermal exposure.  Zcecon  •assumed that 1% of  the  lindane
dust would be passed through dust masks, if they  were worn.

Concerning the  Agency's assumption that 1 gram of fine powder (Bon Ami)  covered
a pair of hands (0.082 m2) ,  Zoecon repeated the experiment using an  inert
agricultural  formulation (Kaolin),  and found that 200 mg (0.2 gran)  completely
whitened  all  surfaces of the hands of an adult male.   In the absence of
contradicting data,  Zoecon also assumed, as did the Agency in PD 2/3, that only
20% of the exposed skin area is actually covered  with lindane dust.

                                   1 22

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Edwards, representing CIEL (comment 194), also presented a  rebuttal  to the
Agency's seed treatment exposure estimates.  First, Edwards disagreed  with-the
Agency's assumption that only lindane dusts are used for seed treatment,
stating that there are a variety of liquid and other formulations  (sane using
"stickers" to improve adhesion) registered for this use.  He also  disagreed
with the Agency's choice of the manual planter box treatment method, arguing
that commercially treated seed and auger treated seed are more cuiinonly used.
According to Edwards, using the mechanized (auger) planter  box method  there is
"virtually no exposure due to seed treatment" if the applicator wears
protective clothing and a face mask during treatment.

Edwards conducted simple experiments similar to those carried out  by Zoecon
which also indicated that 200 mg (0.2 gram) would be a more reasonable estimate
of the anount of formulation to cover a pair of hands than  the Agency1 s PD 2/3
assumption of 1 gram.

Edwards disagreed with the Agency's use of a cotton dust model.  In an area of
1000 m2, there would be 10 grams of dust (using the Agency's 10 mg/m^
assumption), meaning that 40% of the dust needed to treat a bushel of  seed    »
would be in the air, not on the seed.  Edwards does not believe farmers would
be likely to waste so much lindane.  He considered 1 mg/m^  a more  realistic
air concentration to use.  Concerning particle size, Edwards assuned,  as
did Zoecon, that 50% of the lindane dust particles were greater than 30 ug
and therefore too large for inhalation. Also, Edwards used  a formulation
which contained 18.75% lindane (also reccmnended by USDA) rather than
the 25% concentration assumed in PD 2/3.

Estimating the various methods of seed treatment, Edwards assumed  10%  is
treated cuuiercially, 10% is treated by the manual planter  box method,  and 80%
is treated by the mechanized (auger) planter box method.  Rather than  the  one
hour/day assumption made by the Agency for time required to treat  seed, Edwards
assumed that an applicator would have to pour lindane for 2-3 minutes  into the
planter box, refilling the box four times a day, i.e., 10 minutes  of exposure
to lindane per day.

         3.  The Agency's PD 4 Response

The rebuttal comments received by the Agency with regard to this use pattern
were of excellent quality.

Based on information in the Zoecon rebuttal submission, the Agency will
continue to use the manual planter box method as a conservative model  for
estimating applicator exposure during seed treatment.  This is because,
according to Zoecon, commercially treated seed and mechanically treated seed
produce less exposure than seed treated manually.  This assumption is  supported
by the exposure study by Zcecon, during which air concentrations were measured
during "mechanized planter box" treatment.

Based on sufficient evidence submitted to the Agency, it is assumed that
protective clothing is currently being worn during seed treatnent  and  this
protective clothing includes a long-sleeved shirt, long pants, gloves,  and
disposable paper masks (worn during seed treatment and hopper fill operations
only).

                                ' T23"  "

-------
based on  information submitted by Zoecon and Edwards,  the Agency  has  revised
the exposure time estimates made in PD 2/3,  and assumes  that  seed treatment and
hopper  fill  take 10  minutes per day, 2 days  per year.

For estimating dermal exposure, the Agency concurs with  the use of 200 mg of
dust formulation to  cover a pair of hands, rather than the PD 2/3 estimate of 1
gran.   The Agency continues to use the FD 2/3 assumption that of  the  exposed
skin area, 20% would be covered with lindane dust.

Concerning the PD 2/3 choice of 25% active ingredient  as the  most
representative formulation for seed treatment,  the Agency agrees,  based on the
rebuttal  submissions and Agency verification, that the use of an  18.75%  a.i.
dust formulation would be more representative of formulations currently being
used.

Based on  the data in the lindane exposure study submitted by  Zoecon,  the Agency
estimates that lindane air concentrations surrounding  a  planter box would be 2
mg/m3 and 0.01 mg/m3 during seeding.  The Agency accepts Zoecon1s assumption
that 1% of the dust  is passed by the dust mask,  but of the 1%, 100% is
of respirable size.

    3_.	Dog  dusts

        1.   The  Agency's Exposure Calculations in ?D 2/3

Because no actual exposure data were available,  the Agency made the following
assunpticns  to estimate exposure to applicators who apply lindane dust to their
pets: lindane (1% dust)  formulation covered  20% of the exposed skin area; 1
gram of dust completely^covered one pair of  hands; maximum dust inhaled over 2
minute period =  10 mg/nH;  all dust was respirable; no  protective  clothing
was worn; a  treatment took 2 minutes and was repeated  26 times a  year;
and lindane  volatilized at a steady rate for 3  days, at  which time all
lindane would have vaporized.

For estimating respiratory exposure to hone  occupants  after lindane dust
treatments,  the  same assumptions for the dog dip use were made, except that a
typical pet  treatment required 2 oz of 1% powder per treatment, and a resident
would be exposed 12  hours a day, for 3 days, 26  times  a  year.

        2.   Garments on the Agency's PD 2/3  Calculations

Edwards, representing CIEL (cottnent #94)  said that the EPA assumptions should
be modified  the  sane way for dog dust as for seed treatment (also a dust),
i.e. that 5%  of  the  exposed skin would be covered with lindane dust, and that
200 mg  (not  1 gm)  should be used to estimate the amount  of dust that would
cover a pair of  hands.

        3.   The  Agency's FD 4 Response

No special protective clothing is assumed for this use,  i.e.  a short-sleeved
shirt,  long  pants, and no gloves are worn.   If  protective clothing (long-
sleeved shirt, long  pants, and impermeable gloves)  were  worn,  it  is estimated
that dermal  exposure would be reduced by 80%.


                            •-    T24

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As with the seed treatment use, the Agency assumes  that  20%, not  5%,  of the
exposed skin area is covered with  lindane dust.. As  for  the amount  of dust
which covers 2 hands, the Agency accepts the evidence  submitted by  Zoecon and
Edwards (submitted for the seed treatment use)  that  200  mg is more  correct than
1 cm.

Although not submitted as rebuttal evidence, the Agency  has reestimated the
frequency of use .to be twice per year.

To estimate respiratory exposure during the dusting  process using actual data
rather than a hypothetical model,  it is assumed that lindane air concentrations
during the dusting process are comparable to lindane concentrations (2  wg/m?)
surrounding a planter box during lindane (18.75% w/w)  seed treatment  (Zcecon,
1980).  50% of the dust is respirable.  (For explanation of this assumption,
please refer to SEED TREATMENT - the Agency's PD 4 Response).  A breathing rate
of 1.2 ra^/hr for light work is assumed.

For estimating respiratory exposure to home occupants, the sane assumptions
were made for dog dusts as were made for dog dips, except that dogs are dusted
twice a year, not once a year as with the dog dip.                            *

VII.  3ELCW-5KCULDER SPRAYS

    A.  Cucurbits

        1.  The Agency's Exposure Calculations  in PD 2/3

The Agency assumed that exposure to applicators applying lindane to cucurbits
would be conparable to applicator exposure in been (row-crop) spraying  of  the
herbicide paraquat (Staiff et al., 1975), which was  0.4  and 0.001 mg/hr for
dermal and respiratory exposures, respectively.  A 0.06% w/w lindane  solution
was assumed.

        2.  Ccnroents on the Agency's PD 2/3 Calculations

Edwards (comment #94) agreed that  it was reasonable  to calculate exposure  using
the data fron Staiff et al. (1975).  However, he said  the Agency incorrectly
calculated the concentration of paraquat from the Staiff paper: the correct
value being 0.13% w/w rather than 0.025%.

Edwards also said the USDA recommended dose is 1 Ib. of  25% WP in 100 gallons
of water per acre,  not 1 Ub. ai/200 gal/acre as used by  the Agency in the  PD
2/3.

        3.  The Agency's PD 4 Response

No evidence was submitted to the Agency that protective  clothing is routinely
worn by applicators spraying lindane using row-crop  equipment.   If a  long-
sleeved  shirt, long pants, and impermeable gloves were worn, the Agency
estimates that dermal exposure would be reduced by 80%.

The use concentration from the Staiff (1975)  study is  recalculated by the
Agency to be 0.14%.


                                  125

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The Agency  agrees with Edwards that the value for the concentration of  lindane
used  in the ?D 2/3 '-rats too high;  1 Ib.  of 25% WP in 100  gallons  of  water per
acre  is a better estimate (EPA,  1981b).

    3.  Christmas trees - stump-slash applications

        1.  The Agency's Exposure Calculations in PD 2/3

The Agency  assumed that exposure to applicators applying lindane for stump-
slash and trunk treatnaents, using a lew-pressure back pack  sprayer,  would be
comparable  with exposure to applicators applying fenthion using  directed spray
for mosquito  control  (Wolfe et al, 1974).  A use dilution of  0.5% w/w lindane
•was assumed for stump-slash treatment,  and a 0.05% w/w lindane solution was
assured for trunk treatment.   There was a seasonal correction factor of 0.32
cue to reduction of body surface area exposed during the stump—slash treatment
in early spring.

For estimating exposure to applicators making foliar applications to Christmas
trees using hand-gun  pressure sprayers,  the Agency used  the model of Batchelor
and Walker  (1954).  In this study, fruit orchards were sprayed with parathion
in hand-gun pressure  sprayers. A 0.08%  w/w lindane solution  was assumed.
       ;   !
        2.  Garments  on the Agency's PD 2/3 Calculations

Edwards (comment £94)  disagreed  with the Agency's assumption  that two different
types of sprayers are used.  In  his opinion, a grower would use  a back-pack
sprayer for all uses.   Edwards also stated that lindane  use dilutions of 0,1%
for stune-slash and trunk treatments, and 0.05% for foliar  treatments, would be
more  reasonable.   Edwards agreed with the Agency's choice of  Wolfe  et al.
(1974) as a surrogate model.

The U.S. Departoient of Agriculture agreed with the Agency's assumption that
stump/slash applications are normally done using boon crop  sprayers  (refer to
Appendix 1).

        3.  The Agency's PD 4 Response

Sufficient  evidence was submitted to the Agency that protective  clothing is
routinely worn by applicators who spray Christnas trees  with  lindane.
Protective  clothing measures incorporated into the PD 4  exposure analysis
include a long-sleeved shirt, long pants, and impermeable gloves.   It is
estimated that these  orotective  clothing measures reduce dermal  exposure by
80%.
    \                               *
The Agency  uses the back-pack sprayer model as a reasonable conservative model
for its PD  4  estimates,  since the extent of use.of bean  crop  sprayers could not
be verified,  and sines bccm-crcp  sprayers would result in lower  exposure than
back-pack sprayers. The Agency also assumed use concentrations of 6.1% for
stumn-slash and trunk treatments, and G.05% for foliar treatments.
                                     126

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VIII.   PHEPLANT SOIL APPLICATIONS

    A.  Pineapples

        1.  The Agency's Exposure Calculations in PD 2/3

•In  this use,  lindane is injected into  the  soil with a fumigant before
planting.  Based on an exposure analysis for a similar use of EBCP,  the Agency
assured that  the primary route of exposure was by inhalation, and that at the
low concentrations of pesticide applied, vapor concentration levels  in air
above soil were a direct function of the vapor pressure.   After the  lindane is
injected, the field is covered with a  plastic mulch,   potential for  exposure
depends en duties performed  (equipment operator,  mulch operator,  or  supervisor)
during  an assumed 14-hour working day.  However,  the anticipated hourly
exposure associated with any of these  functions was very  small (approximately
5 X 1(T7 mg/hr).
         2.  Carments on  the Agency's PD  2/3  Calculations
Edwards  (consent #94) disagreed with  the assumption that the loss  of lindane
froa soil  is directly dependent upon  its vapor pressure, as this does not take
into account the absorption of lindane  into  organic and  clay fractions of soil,
which occurs rapidly and would lower  volatilization considerably.   Considering,
however, that  the  "worst-case" value  of 4.9  X  10~7  mg/hr is so small, Edwards
felt that  it was not worth modifying.  EPA's PD  2/3 calculations.

         3.  The Agency's PO 4 Response

The calculations made in the PD 2/3 remain unchanged for the PD 4.

IX.  HOUSEHOLD PRODUCTS (criHHK)

    A.   Flea collars

         1.  The Agency's Exposure Calculations in PD 2/3

The Agency made the following assumptions to estimate exposure to  pet owners
and hone occupants during the use of  lindane-treated flea collars:   lindane was
released at a  constant rate for 6-8 weeks; because  lindane (0.61%)  was
incorporated into  the collar rather than on  the surface  of the collar, denaal
exposure was considered to be negligible; data for  5% DDVP incorporated into
cat collars could  be extrapolated for lindane,  i.e.  the  concentration of DDV?
in the air of  a roan housing one animal wearing one 5% collar was  0.35 ug/m^
(Shell Chemical Company, 1976); there was no difference  in the volatility of
lindane  and DCVP;  a dilution factor of  10 to corpensate  for difference between
the DDVP studv roan (48 nP) and a standard living area (480 m^); a  breathing
rate of  1.2 m^/hr; a person would be  exposed 24 hours/day,  365 days/year;  a
lung absorption factor of 100%.

         2.  Comments on the Agency's  PD 2/3  Calculations

Edwards, representing CIEL (counent $94), disagreed with the assumptions that
lindane and DDVP volatilized at the same rate,  and  that  a person would be
exposed  to such vapors for 24 hours/day, 52  weeks/year.   Edwards suggested


                              =."     127"	

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using  no more  than 16 hours/day,  48 weeks/year.

        3.  The  Agency's PD 4 Response

The first three  assumptions niade  in the PD 2/3 remain unchanged for the  ?D 4.
However, the Agency reevaluated the data in the DDVP study, which gave the
range  of concentration of DDV? in the air of a roan housing one animal with one
collar to be 0.00013 - 0.0031 mg/ra^, with a mean value of  0.0016 mg/m3
(Van Kanper et al.,  1977).   For the PD 4, this mean value  is used.

The Agency disagrees with Edwards'  connsnt about vapor pressure differences
being  significant,  because for this use each chemical is incorporated into the
collar and formulated to be released slowly.

The room dilution  factor of 10 is retained.  For this use, a factor of 3 air
changes per hour is not included  in the calculations, because  the DDVP ream
where  the study  was conducted already had a high air exchange  rate.

The Agency assumes that a person  would be exposed 15 hours a day, 365 days a
year,  and would  have a breathing  rate of 0.68 m^/hr.  (For an  explanation
of these assumptions, please refer to SHELF PAPER - The Agency's ?D 4
Response.) Because it is assumed  that the lindane would be in  a vaporized
state,  the 100%  lung absorption factor is retained.

    5.  Shelf  oacer
        1.  The Agency's  Exposure Calculations in ?D 2/3

The Agency made the  following set of assumptions: innalation was the primary
route of exposure; after  105  days,  40%  of- the lindane had vaporized; a 12-foot
roll of shelf paper,  containing 15  mg lindane^per ft2, was used to  treat
three 4x4x3 meter rccres;  a person had a 1.2 ra^/hr breathing rate; the
dermal exposure was  considered very small and unquantifiable (therefore
no dermal exposure was  assumed) ;  exposure occured 24 hcurs/day, 105
days/year; one roll  of  lindane- treated  shelf  paper was used per year;
and 11 million people were exposed.

        2.  Comments  on the Agency's PD 2/3 Exposure Calculations
Edwards, representing cr^i,  (comment  394),  criticized  the Agency fcr not
including air exchange  rates,  and for assuming  continual exposure by the
occupants.  Rather  than the Agency's hypothetical model, Edwards reccnroenced
using the data  in Queen (1953),  where lindane was  released  fron a vaporizer at
a rate of 1 mg/24 hrs/1300  ft3 into  a closed  roan,  giving lindane air
concentrations  of 0.4 - 0.5 ug/1 of  air for 100 days.  Using the Queen data and
EPA 's assurrotion that <*C% of the lindane from a 12  ft2 roil of shelf paper
vaporized into  three rooms  4x4xS meters in size, Edwards estimated a lindane
air concentration of 0.026  ug/nt3.  He further assumed = 1.2 irP/hr breathing
rate, that 16 hours a day would be scent indoors,  and that  exccsure would last
105 days.

Paper Products, Inc. (comment £93) said that:  the Agency should have accounted
fcr air turnover in the treated dwelling,  and suggested that the Agency use 3
air exchanges per hour  as a conserva.ti.ve. estimate  (which had been used by- the



                             '.    128

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Agency  for other uses  in' the ?D 2/3).  Also,  the. formulation of its shelf paper
has been changed to  include the use of a  new  resinous binder that dissolves the
lindane and holds  it on  the paper, with 27.12%,  not 40%,  volatilizing in 105
days.   Concerning  breathing rates, Paper  Products felt it was unreasonable for
the Agency to assume that a person would  be engaged in light work (1.2 rn^/hr)
for 24  hours a day,  and  that a  breathing  rate of 0.2S2 mVhr was more reasonable.

•Millen  Industries, Inc.  (comment #112) and Athena Products Corporation (comment
*102) submitted identical rebuttal comments for  the lindane-treated shelf paper
use.  They argued, based  on the data contained in the report entitled
"Determination of  Lindane in Air of a Closed  Rccm" (submitted to the Agency
after the  publication of  the PD 1) that 8 air exchanges per day,  and 0.000004
mg/hr for  respiratory  intake, would be more reasonable.

        3.  The Agency's  ?D 4 Response

The model  in the PD  4 utilizes  a study conducted on a mothproofing product not
registered in the U.S. (Haag and Pruggroayer.,  1981). .  In this study, average
lindane air concentrations were measured  inside  a closed  wardrobe (0.4
mg/m^), and in the outside roan air but with  no  ventilation (0.002 mg/m^).
A  ratio of inside  to outside concentrations is used.                            *
                                                                                i

In the  study submitted by Millen Industries,  a lindane air concentration inside
a  closed cabinet, 9  days  after  being lined with  shelf paper containing 31 mg
lindane/ft^, was 0.4 mg/m^.  This value is then  multiplied times  the ration
established in the Celanerk study to" give a better estimate for the actual
lindane air levels which might  be expected from  the shelf paper use.

The Agency agrees  that a  consistent air exchange rate should be used for all
the indoor uses of lindane.  Therefore, for the  PD 4,  the Agency  is using 3 air
changes per hour.

The issue  was raised by various registrants that for hone uses of lindane it
was unreasonable to  assume that  residents would  spend  24  hours a  day,  365 days
a  year  indoors.  To  estimate a more reasonable number,  realizing  that there
would be many exceptions,  the Agency uses an  estimate  of  15 hours per day
(Leary et  al., 1974) as representative time spent for  the average resident
indoors.   The 365 days/year estimate was retained for  the shelf paper use,  for
lack of evidence submitted to the contrary.

Concerning representative  breathing rates for a  person indoors, the Agency
agrees  that it is unlikely that a person would be engaged in light work for the
entire 15  hours/day  the Agency  has assumed is  scent indoors.   Therefore,  a  more
representative average breathing rate of 0.63  rn^/nr (3  hours at 1.2 ra^/hr,
and 12 hours at 0.5 m^/hr) is used.  This breathing rate  is used  where
appropriate throughout the ?D 4  exposure calculations.

    C.  Household sprays

        1.  The Agency's  Exposure Calculations in PD 2/3

Because no actual exposure data  were available,  the Agency mace the following
assumptions in estimating a person's exposure  to household sprays:  a  coarse
spray (0.1% w/w lindane)   has 0;01% particles  (respirable  size) between 40 and"

                              -     129

-------
60 microns,  and  0.17%  between 40 and 100 microns,  with 95%  of  the  spray  being
deposited on surfaces;  a 12,000 ft 3 house has 12 02 applied over a 5 minute
period, ones a year; there is no dermal exposure;  0.1% of the  spray is
respirable;  there  is a breathing rate of 1.2
        2.  Ccmnants  on the Agency's PD 2/3  Calculations

Edwards,  (content $94), agreed with the model and assumptions  used by  the
Agency, except  that Edwards assumed 50% lung absorption rather than 100%,

        3.  The Agency's ?D 4 Response

A recent  study  was submitted to ths Agency by the Penick Corporation, which
nseasured  dennal and respiratory exposures to hons applicators  using resssethrin
formulated' in a pressurized container.   In the Agency's opinion, this  is a
reasonable model  to use to estimate homeowner exposure to  lindane sprays.

Unlike the FD 2/3, but  consistent with the pet use assumptions , exposure to
residents after using lindane household sprays is included in  the ?D 4 for all
applicable horns uses.   After a household spray is used, it is  assumed  that
there is  potential for  resident exposure over a  three-day  period, at which time
all the lindane will  be vaporized.   All of the vaporized lindane is assuned to
be respirable.

Other assumptions (please refer to  SHELF PAPER - The Agency's  PD 4 Response)
include the following :  residents spend an average of 15 hours  per day  indoors;
there are 3 air changes per hour; an average breathing rate is 0.64 rn^/hr.
                                    130

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        APPENDIX IV:
Icr^Y TESTS o? LJNCANE: SUMMARY TABLE
             131

-------
STUDY TYPE ORGANISM/TISSUE
I. GENE MUTATION Salmonella typh.
Salmonella typh.
Salmonella typh.
Salmonella typh.
MODE
Ames
Ames
Ames '
Ames
REPORTED
RESULTS
Inconclusive
TA 1538 PCS
at toxic coses
NEC*
NEG
INVESTIGATORS
Ercegovich & Rashid
(1977)
Rchrbcm (1S77)
Lawler et al. (1979)
Purchase et al.
II. CHPCM3SCME
    ABERRATIONS:
                        Salmonella typh.      Ames
                              NEG-
                        Salmonella typh.      Ames      "Equivocal'
                        Saccharcmyces cere.   Ames

                        Saccharonyces cere.   Ames

                        Mcuse/G  46;  A 21      HKA
                       Mcuse/TA 1535
                     HMA
                       Drcscchila malanc.    SLRL
Human lymphocytes/  in vitro
rat fibroblasts

Human lymphccytes   in vitro
                       Cn. hamster cells    in- vitro
                       Rat/Bone marrow       i p
                         (beta-i saner)

                       Ch. hamstsr/Bcne      i g
                         marrow
                              NEG

                              NEG

                              NEG
POS at toxic
doses

NEG
Deer. MI/
(incr. CA)

(PCS «tid)
3R at toxic
  doses

('tid BR at
 toxic doses)

 POS for C3
                                 NEG
                              (1000 ADI!
   (1978)

van Dijck & van der
  Vcorde (1976)

Gapalaswamv et al.
  "(1980)

Schubert (196*))

Shalin (1977)

Suselmaier et al.
   (1972)

Rchrbcm (1976)
                                                 Benes and Srsm
                                                    (1969)
Zimcnjic et al.
   (1981)

Tzcneva-Maneva
        (1971)
Ishidate & Cdashima"
    (1977)

Shimazu et al.
    (1976)

Rohrborn (1976)
*NEG = negative
                                          132

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                  APPENDIX IV: continued
Mouse/Bone marrow,
gem cells
Rat/Ecne marrow
Guinea pig/Germ
cells
Human lymphocytes
Rat/Fetuses
: Rat/Fetuses
Rat/Fetuses
Rat/Fetuses
Rat/Fetuses
Rat/Fetuses
Mouse/Pill's
« (Micrcnuclei)
III. DMA Salmonella typh. '
REPAIR
Bacillus subt.
Salmonella typh.
1 Rat thymocytes;
human lymphocytes/
UDS; CNA synth.
i g
"oral"
dermal
Exposed
vtcrkers
DLT
DLT
DLT
DLT
DLT
DLT
i g
Diff. tox.
Diff. tox.
Diff. tox.
jLn vitro
(?NBG)
(7NBG)
NEE
NEC
(PCS?)
NEE
NEC
NEE
NEC
NEC
NEC
NEC
NEC
NEE
PCS at
toxic
doses
Transf. human cell
line (VA-4)/UBS

Rat/Mouse HPC/UDS
in vitro
in vitro
NEE
NEC
                                                        Nigara et al  (1981)
                                                        Shtanncv et al.
                                                          (1980)

                                                        Dikshith et al.
                                                          (1973)

                                                        Kiraly et al. (1975
Carey et al.  (1975)

Rohrtoorn (1977)d

Reno (1976)

Gencik  (1977)

•Buseimaier et al.
  (1972)

Epstein et al.
  (1972)

Jenssen & Ramel
  (1980)


Lawler et al. (1979!


Shirasu et al. (197-1

van Dijck et al. (IS

Rocchi et al. (1980)



Ahmed et al. (1977)
                  *.

Probst et al. (1981)
                        133

-------
                                    APPENDIX IV:  continued
 IV*.   OiliER

.giant Cytology;
Algal cell division

Algal call division

Algal cell division

Aliiurn cepa root
 tips

Zea raays root  tips
                    Pisum sativun
Manual i an Cells:   MD/3-I6 HeLa/HESF      in vitro
                     cell lines
                    Hat liver cells         in vitro
Cell Transfor-
mation:'
PCS

PCS

PCS

PCS for
c-iidtcses

PCS for
deer. DMA
syhth/mi-
tosas

Poly-
 ploidy

NEC for
mtiltinu-
cleaticn

INCR. MI/
tetraploicy
Jeanne (1979)

Das & Singh  (1978)

Kar & Singh  (1979)


Nyborn (1947)

Anderegg et al.
  (1977)


                  »
Baoar et al. (1971)
                                                 deBrabander et al.
                                                   (1976)
                                                 Hitachi et al.
                                                   (1975)
BHK21/WI-3S/Chang      in vitro'
MEG
Purchase et al.
  (1978)
                                           134

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                                APPENDIX V
                          List of Abbreviations
a. i.     active ingredient
CAG      Carcinogen Assessment Group
CFH      Code of Federal Regulations
CUSL     Centre International d1Etudes du Lindane - a non-profit international
         scientific study .group on lindane, established in 1969 and organized
         under the laws of Belgian.  Masters are nine conpanies which
         manufacture lAndane.
EPA      U.S. Envi rooms.-ntal Protection Agency
FIFHA    Federal Insecticide, Fungicide and Fcdenticide Act, as amended  (7
         U.S.C. 136 et seq.)
FR       Federal Register
FY       Fiscal Year
PD       Position Document
ppra      parts per million
RPAR     Rebuttable Presumption Against Registration - a process, carried cut
         by the Office of Pesticide Programs in EPA, to gather and analyze data
         on the risks and benefits of registered pesticides,
SAP      Scientific Advisory Panel-
USDA     U.S. Department of Agriculture
wp       wettable pcwcer
w/w      weight per weight
ug       microgrsn
                                   i 55

-------
                         COMMENT RHJr'i^ENCES*
                              (3000/10C)
 ccmnent number          submitted by

    91           National Association of vfoeat Growers
    93           Paper Products, Inc.
    94           Centre  International d1Etudes du Lindane
    102          Athena  Products Corporation
    104-109      Trout Unlimited
    112          Miller.  Industries, Inc,
    115          Janette Sherman, M.D.
    134          Chapman Chemical Company
This list includes only  those Garments received by EPA following
issuance of PD 2/3 and cited in I'D 4.  All comments received by EPA
are available for review in the public file located in the Document
Control Office, roan 106  East Tower, 401 M Street, S.W. / Washington,
D.C. 20460.
                               136

-------
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-------
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                                   138

-------
    EPA,  19S2b.   U.S. Environmental Protection Agency. Environmental Fate Branch,
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                                     139

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 Hayes,  W.J.,  1975.   Toxicology of Pesticides.  Williams and Wilkins  Ccnipany:
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 Ito, N. , H. Nagasaki, M. Arai, S, Makiura, S. Sugihara, and K. Hirao.  1973.
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 Johnson, D.W.  1982. Letter, 11 Jan 1982 from Mr. Johnson,  Supervisory
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 ' EPA.

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  toxicity of a popular scabicide.   Cl in.' Pharmacol.  Ther.  27(2) :149-155.

                                      140"

-------
 Laut, J., 1982.  Personal communication on 1/9/82 between Mr.  J.  Laut,
 Colorado State Forest Service,  and J.  Jensen,  Chemist,  EFB,  HED,  GPP,  EPA.

 Lavy, T.L.,  J.S.  Shepard, and J.D. Mattice,  1980.  Exposure  measurements of
 applicators  spraying (2,4,5-trichlorophenoxy)  acetic acid in the  forest. J_._
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 Leary, J.S., W.T.  Keane,  C.  Fontenot,  F.  Feichtmeir, D.  Schultz,  B.A.  Kocs, L.
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 Environ. Health.   29: 303-314.

 Litterst, C.L., and E.  Miller,  1975.   Distribution of lindane  in  brains  of
 control and  phenobarbital pretreated dogs  at the  onset  of iindane-induced
 convulsions.   Bull. Environ. Contsm.   13:619-624.

 Maddy, K.T., L. Johnston, B.  Cusick, F.  Scheider, T. Jackson,  C.  Cooper, A.S.
 Frederickson, 1979.  A study in southern California in  July  1979  of the
 potential dermal and inhalation exposure of  applicators and  other persons who
 might later  enter or occupy  areas treated  with chlordane used  against
 subterranean termites under  houses. Field Study-Report Number 683.  Worker
 Health and Safety Unit, Division of Pest Management, Environmental  Protection
 and Worker Safety/ California Department of  Food  and Agriculture, Sacramento,
 California.

 Mansuy, D.,  P. Beaune,  T. Cresteil, M.  Lange,  and J. Leroux.   1977.  Evidence
 For Phosgene Formation During Liver Microscmal Oxidation of  Chloroform.
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 Mauer, I. 1933.   NRDC's  comments about mutagenicity testing of lindane
 (Lindane Draft PD 4).  Memorandum:  8  Aug. 83  to  Off. General  Counsel. EPA.

 Memo, 1978a.  Application techniques data  (cucurbits -  Florida) dated May 17,
 1978.  Fran  Mike  McWhorter,  Entomologist,  EEB, to Julian Donoso,  Chemist, EFB,
 HED, OPP, EPA.

 Memo, 1978b.  Estimates of (forestry)  workers  exposed to lindane, dated  June 9,
 1978.  Economics Analysis Branch,'  Criteria  and Evaluation Division, OPP, EPA.

 Memo, 1980a.  Degree of.personal protection  afforded by  specific  types of
 protective clothing,  dated July  14,  1980.  From V.  Kozak, Chemist, EFB to D.
 Brooks, P. Cammer, and  S. Roan,  SPRD, OPP, EPA.

 Memo, 1980b.  Study (draft)  on a population  exposed  to  lindane through use  of
 room vaporizers, January  4,  1980.   From A. Nielson,  Coordinator for Special
 Projects, EEB to V. Kozak, Chemist,  EFB, HED,  OPP,  EPA.

'Memo, 1980c.  Breathing rates for inhalation exposure assessment  (draft),
 April 4, 1980.  From D. Severn,  Chemist, EFB to Chief, SFB ann EFB staff, EFB,
 HED. OPP, EPA.

 Memo, 1932a.  Lindane PD  4 Assessment.  Dated  March 30,  1982,  from Robert E.
 McGaughy (Carcinogen Assessment  Group)  to John W.  Melone (Director,
 Hazard Evaluation  Division).

 Memo, 1982b.  Review of a Draft  Position Document 4  on Lindane.  Dated August
                                141

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5, 1982, frcm Roger Gardner  (Toxicolcgist) to Anne Hollander (Lindane Project
Manager).

Memo, 1982c.  Lindane Toxicity.  Dated November 19, 1982, from William L.
Bumam  (Deputy Chief, Toxicology Branch) to Anne Hollander (Lindane Project
Manager).

Memo, 1982d.  Lindane H>4:  Mutagenicity Testing Requirements.   Dated
October 21, 1982,  frcm  Irving Mauer  (Geneticist) to Amy Rispin (SIS).


Memo, 1982e..  Toxicology Review of Lindane PD 4.  Dated Decamber 3, 1982,
frcm Anne Hollander (Lindane Project Manager, SPRD) to Roger Gardner
(Toxicolcgist, BED).

Memo, 1982f.  Dermal Absorption of Lindane.  Dated June 2, 1982, frcm Orville
E. Paynter  (Branch Chief, Toxicology Branch, BED) to Janet L. Auerbach (Branch
Chief,  Regulatory  Support Branch, SPRD).

Memo, 1982g.  Lindane FD 4 Risk Analysis.  Dated May 26, 1982 from Anne
Hollander (Lindane Project Manager)  to Christine Chaisson (Section Head,
Toxicology Branch).

Memo, 1982h.  Lindane residues fron  various bodies of water in Delaware.
Dated June 11, 1982, frcm Harry Craven (Ecological Effects Branch) to Anne
Hollander (Lindane Project Manager).

Memo, 1982i.  Lindane Exposure Assessments Required for Label Restrictions/
Negotiations.  From Joseph C. 'Reinert (Environmental Fate Branch)  to Anne
Hollander (Lindane Project Manager).

Memo, 1983a.  Review of the  Paper: Proconvulsant Effects of Lindane Enhancement
of Amygdaloid Kindling  in the Rat.   Dated January 18, 1983 frcm Robert P.  Zendzian
(Toxicolcgist) to  Anne Hollander (Lindane Project Manager).

Mohrmann, R. , and  R. Weissberger, 1977.  Comparison of physical and behavioral
effects  and bleed  levels in  weanling rabbits treated with Kwell lotion and
placebo  lotion.  Reed & Carnrick Pharmaceuticals, report % 77076,  Kenilworth,
N.J.  (Unpublished).

Morgan,  D.P., 1980.  Iowa Epidemiologic Studies Program: Lindane Special
Study.   University of Iowa,  College of Medicine, Department of  Preventive
Medicine and Environmental Health, Iowa City, Iowa.  Final Report on EPA
contract 68-01-4126.

Morgan,  D.P., E.M. Stockdale, R.J. Roberts, and A.W. W<er,  1980.  Anemia
associated with exposure to  lindane.   Arch. Environ. Hlth.  35(5):307-310.

Nagasaki, H., S. Tonii, T. Mega, M. Marugami, and N. Ito.  1972.   Eepato-
carcinogenic effect of alpha-, beta-, gamma-, and delta- isoners of benzene
hexachloride in mice.  Gann. 63:  393.
                                   142

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Naishtein, S.Y., and D.L. Leibovich, 1971.  Effect of small doses of DDT and
lindane and their mixture on sexual function and anbryogenesis in rats.
Hyg. Sanit.  36(4-6):190~194.

NCI, U.S. H.3.W. National Cancer Institute, 1977.  Bioassay of lindane for
possible carcinogenicity.  Carcinogenesis:  technical report series no. 14.
CAS no. 53-89-9.  NCI-CG-TR-14., Bethesda, Md.

NCI, U.S. H.E.W. National Cancar Institues. 1979 Bioassay of 2,4,6-
Trichlorophenol for Possible Carcinogenicity. Carcinogenesis Technical
Report Series. No. 155. CAS No. 88-06-2. NCI-CG-TR-ISS., Bethesda, Maryland

Nielsen, D.G., 1982.  Personal communication on 1/9/82 between Dr. D.G.
Nielsen, Department of Entomology, Ohio Agriculture Research and Development
Center, and J. Jensen, Chsnist, EFB, HED, OPP, EPA.

NRDC, Natural Resources Defense Counsel.  1983.  Ccnroents of the Natural
Resources Defense Counsel en Lindane Position Document 4-Draft 23 February
1983.  prepared by Lawrie Hott, M.S., 10 June 1983.  24 pp unpubl.

Oesch., F.  1980.  Bacterial Mutagenicity Tests of Lindane With Mouse
Liver Preparations As Metabolizing Agents.  Exhibit 15, 22pp in:  C.I.E.L.
Lindane Response of the Centre International d'Etudes du Lindane to EPA's
Preliminary Notice of Determination and Position Document 2/3 on Lindane.
Vol. II.  Printed 1981. K. Schillinger Verlag und Druckererei.               »

Ortega, P., W.J. Hayes Jr., and W.F. Durham. 1957.  Pathologic changes in
the liver of rats after feeding low levels of various insecticides.  A.M.A.
Arch. Path. 64:  614-622.

Palmer and Lovell, 1971.  (Confidential, unpublished).

Palmer and Neuff, 1971.  (Confidential,.unpublished).
Palmer et al., 1971.  (Confidential, unpublished).

Penick Corporation, 1980.  Penick Corporation Assessment of Inhalation and
Dermal Exposures to SBP-1382 (Resmethrin).  Reported by P.M. Roncetti, dated
1980.  Permission granted by Dr.  M. DeVries, Penick Corporation,  for the Agency
to use the data from this study.   Requests for this study should be made
directly to Dr. de Vries. (Confidential, unpublished).

Petrescu, S.T., V. Dobfe, M. Leibovich, Z. Petrescu, and S.A. Ghelberg, 1974.
Studies of the effects of long-term administration of organcchlorate pesticides
(lindane, DDT) on the white laboratory rat.  Rev. Med. Chirurg.,  lasi (4).

Pohl, L.R., B. Bhooshan, N.F. VSiitaker, and G. Krishna.  1977.  Phosgene:
A Metabolite of Chloroform.  Biochem. Biophys. Research Cormunic.  79:
684-691.

Pohl, L.R. , R. Branchflower, R. Highet, J. Martin, D. Nunn, T. Monks, J.  George,
and J. Hinson.  1981.   The Formation of Diglutathionyl Dithiocarbonatee as a
Metabolite of Chloroform, Brcmotrichloromethane, and Carbon Tetrachloride.
Drug Metabolism and Disposition.   Amer. Soc, Pharmacol. Excerim.  Theraoeutics.
9:  334-339.

Portig, J., P. Krauss, K. Stein,  W. Koransky, G. Noack, 3. Gross, and
S. Sodomann.  1979.  Glutathione Conjugate Formation From Hexachloro-
cyclohexane and Pentachlorocyclohexane by Rat Liver, In Vitro.  Xenobiotica.
353-378.
                               143

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 Pritcr.ard,  J.A., 1976.  A guide to industrial respiratory protection.   HEW
 Publication No. (NIOSH)  76-1S9.

 Public Health Service, 1952.  Evaluation of public health hazards associated
 with the use of economic poisons.  U.S. Public Health Service,  Center  for
 Disease Control Technical Development Branch, Savannah,  Georgia.   Project No.
 74-T-ll.

 Reno.   1976 a and b.  (Confidential, unpublished).

 Rieter, L.W.  1982.   Review of a Study:  "Neurotoxicological Effect of Snail
 Quantities  of Lindane."  attached to letter, 27 Oct.  1982.   Health Effects
 Research Lab., Res.  Triangel Park., N.-W., USEPA.

 Sipes, I.G., G. Krishna, and J.R. Gillette.  1977.  Bioactivaticn of Carbon
 Tetrachloride, Chloroform, and Bronctrichloranethane: Role  of  Cytochrane
 P-450.  Life Sci.   20: 1541-1548.

 St.  Grsr, V., 1971.   Investigations into mechanises responsible for seizures
 induced by  chlorinated hydrocarbon insecticide: the role of  brain arzronia
 and  glutanine in convulsions in the rat and cockerel. J.  Neurochem.   18:365-374.

 Schwartz, F., and H. Kaschowitz, 1968.  Das hinsnerelectroretincgranm des  frosches
 unter der einwirkung von -hexachlorozyclchexan.  Acta. Biol.  Med.  Germ.
 21:  205-212.

 Savage, E.P., T.J. Keefe, and H.W, Wieeler, 1979.  National  Household  Pesticide
 Usage Study, 1976-1977:  Final Report.  Epidemiolcgic Pesticide Studies Center,
 Colorado State University, Fort Collins, Colorado..

 Severn, D., 1978.   Analysis of human exposure to DSC?, date  March 27,  1978.
 Chemistry Branch,  Criteria and Evaluation Division, OPP, EPA.

 Solomon,  L.M., D.P.  West, J.F. Fitzloff, and A.M. Backer,  1971.   Gamma benzene
 hexachloride in guinea-pig brain after topical application.   J. Invest.
 Dermatol.  68:310-312.                     -

 Staiff, D.C., S.W.  Comer, J.F. Armstrong, and H.R. Wolfe, 1975.   Exposure to
 the  herbicide paraquat.  Bull. Snv. Contam. Tox.,  Vol.14, No.  3:  334-340.

 Starr, H.G. , and N.J. Clifford.  1972 Arch. Environ.  Health.  25:  374-375.

 Thorpe, B./ and A.I.T. Walker, 1973.  The toxicology  of  dieldrin  (HEOD) ,  II.
 Comparative long-term oral toxicity studies in mice with dieldrin, DDT, pheno-
 barbitone,  B-BHC and a-BHC.  Fd. Cosmet. Toxicol.  11:433-442.

 Trivonva, T.K., I.N. Gladenko, and V.D. Shulyak, 1970.   Effect  of ganrra BEC
 and  serum on reproduction.  Veterinariya 47(6):91-93. Abstracted in 1973.
^Evaluation  of sane pesticide residues in feed, 1974.   World  Health Organization.

 Truhaut,  R.  1954.  Communication au symposium intern, de la prevention
 du cancer,  Sao Paulo,  in:  Food and Agricult.  Organiz. World  Health  Organiz.
 1967.   Evaluation of seme oesticide residues in feed.
                                144

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 Tzonera-Maneva,  M.T.   1971.   The Influence of Diazinon and Lindane on the
 Mitotic Activity and' Karyotype of Human Lymphocytes Cultivated _In Vitro.
 Heanatol.   38:   44-347.
 USDA, 1980.  Lindane rebuttal response submitted to D.M.  Costle,  Administrator,
 SPA (Reprinted  in full in Appendix I).

 USDA/EPA,  1978.   Preliminary Benefit  Analysis of Lindane.  A joint draft
 reprot prepared  by EPA and USDA.

 U.S.  Department  of Health, Education,  and Welfare.   1974.  Criteria for a
 recoisnended standard.. .Occupational Exposure to Cotton Dust.   HEW Publ.  No.
 (NICSH)  75-113.   Washington",  D.C.

 Van Bladereu, P.J./ D.D.Breimer, G.M.F.  Rotteveckmijs,  P. de Kniff, G.R.
 Mohn, B. van Meeterenwalchli, W. Buijs,  and A.  van  der Gsn.   1981.
 The Relation Between the Structure of Vicinal Dihalogen Compounds and Their
 Mutagenic  Activation via Conjugation  to Glutathione.   Carcincgenesis.  op
 499-505.
 i                             i
 Van Kampen, K.R.,  D.R. Brooks and S.D.  Allen,  1977,   Influence of high
 temperature and  low hunidity on cats  wearing single and multiple  ciclcrvos flea
 collars.   Report by Intermountain Laboratories,  Inc.,  Midvale, Utah,  for  Shell
 Chemical Company.   Requests  for this  study should be made directly to Mr.  Ed
 Hobson,  Shell Chemical Company,  Washington,  D.C.  (Unpublished).

 WARF  Institute Inc.  1970.  Methodology for Smc-Cloud  Lindane Test.  Report
 No. 0102118.  Madison, Wise,   (unpublished).

 Weaver,  M.A., 1977.  Water pickup on  the skin.   Unpublished study cited with
 the permission of Dow Chemical Company,  Midland,  Michigan.
 Williams,  L., 1981.  Personal communication on 2/9/81  between 1.  Williams, USDA
 Southern Forest  Experiment Station and  J.  Jensen, Chemist,  EFB, BED,  OPP,  EPA.

 White, G.L.,  and M.G.  Larrabee,  1973.   Phosphoincsitides  and other phospholipids
 in sympathetic ganglia and nerve trunks of rats:  Effects of neuronal activity
 and incsitol analogs (beta-  and gamma-hexachlorocyclohexane)  (Lindane)  on
 (32?)  labelling,  synaotic transmission,  and oxonal  conduction.  J.  Neurochem.
 20:783-798.

 Wolfe, H.R.,  K.C.  Walker,  J.W.  Elliott,  W.F.  Durham, 1959.   Evaluation of the
 health hazards involved  in in-house spraying  with DDT.  Bull.  World Hlth.  Ora.
 '20: 1-14.

 Wclfe, H.R.,  J.F.  Armstrong,  and W.F. Durhan,  1974.  Exposure of  mosquito
 control workers.   Mosquito News, Vol 34,  No.  3:  263-268.

 Woolridge,  W.S.,  1948,   The  gamma iscmer of hexachiorocyclohexane in the
 treatment  of  scabies.    J. Invest.  Dermatol.   10:236-266.

 Zendzian,  R.  1983.  Memorandum to A. Hollander,  1  Jan. 1983,  regarding a
 review of  the paper:   Preconvulsent Effects of  Lindane Enhancement  of Amyg-
 daloid Kindling  in the Rat.   Toxicol. Branch.,  Hazard  Evaluat. Div. OPP.
• USEPA.


                                    45

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•Zoecon,  1980.  Lindane  seed  treatment: A risk-benefit analysis.   Centre
International d'Etudes  du  Lindane  (CIEL) rebuttal cotinent 94(3COOO/10c).
                                                                     L
Zcecon,  1981.  Hardwood lumber worker exposure to lindane during green  chain dip
lindane  treatment of hardvvcod, Septanber 15-15, 1981.
                                 146

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