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)
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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
-------
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
-------
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
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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
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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
-------
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
-------
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.).
-------
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
-------
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.
-------
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
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- 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
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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
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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
-------
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
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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.
-------
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.
-------
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
-------
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
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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.
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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
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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.
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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.
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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
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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
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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.
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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.
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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
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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.
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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.
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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.
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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."
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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."
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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.
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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 ; »
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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.
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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
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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 «*>
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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.
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APPENDIX II:
Garments fran the Science Advisory Panel
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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.
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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
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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
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APPENDIX III:
EXPOSURE ANALYSIS
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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. !
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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.*
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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 •
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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
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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
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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
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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
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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).
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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%.
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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.
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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"
-------
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
-------
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
-------
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
-------
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
-------
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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138
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140"
-------
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5, 1982, frcm Roger Gardner (Toxicolcgist) to Anne Hollander (Lindane Project
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