[Federal Register Volume 59, Number 53 (Friday, March 18, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-6280]
[[Page Unknown]]
[Federal Register: March 18, 1994]
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ENVIRONMENTAL PROTECTION AGENCY
[OPP-30000/10H; FRL-4760-6]
Lindane; Proposed Decision not to Initiate a Special Review
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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SUMMARY: This notice announces EPA's proposed decision not to initiate
a Special Review of pesticide products containing lindane. A Special
Review was proposed based on contentions of irreversible kidney effects
from certain lindane exposure. EPA has determined that the kidney
effects observed are specific to the male rat and are not relevant to
human health risk assessment; therefore, a Special Review is not
appropriate.
DATES: Written comments, identified by the document control number OPP-
30000/10H, must be received on or before May 17, 1994.
ADDRESSES: By mail, submit comments to: Public Response and Program
Resources Branch, Field Operations Division (7506C), Office of
Pesticide Programs, Environmental Protection Agency, 401 M St., SW.,
Washington, DC 20460. In person, deliver comments to: Rm. 1128, Crystal
Mall #2, 1921 Jefferson Davis Hwy., Arlington, VA.
Information submitted as a comment concerning this notice may be
claimed confidential by marking any part or all of that information as
``Confidential Business Information'' (CBI). Information so marked will
not be disclosed except in accordance with procedures set forth in 40
CFR part 2. A copy of the comment that does not contain CBI must be
submitted for inclusion in the public record. Information not marked
confidential may be disclosed publicly by EPA without prior notice. All
written comments will be available for public inspection in Rm. 1128 at
the address given above, from 8 a.m. to 4 p.m., Monday through Friday,
except legal holidays.
FOR FURTHER INFORMATION CONTACT: By mail: Brian Steinwand, Special
Review and Reregistration Division (7508W), Office of Pesticide
Programs, Environmental Protection Agency, 401 M St., SW., Washington,
DC 20460. Office location and telephone number: Special Review Branch,
Rm. WF32G5, Crystal Station #1, 2800 Crystal Drive, Arlington, VA.
Telephone: 703-308-8174.
SUPPLEMENTARY INFORMATION: This notice announces EPA's decision not to
initiate a Special Review of lindane (gamma-hexachlorocyclohexane) and
sets forth the rationale for this proposed decision. In summary, EPA
has reevaluated the concerns raised in the September 18, 1985
preliminary notification to registrants and applicants in light of
subsequent relevant information. Based on this review, EPA has
determined that a Special Review of lindane is not warranted based on
its effects in the male rat kidney.
I. Introduction
A. Legal Background
A pesticide product may be sold or distributed in the United States
only if it is registered or exempt from registration under the Federal
Insecticide, Fungicide and Rodenticide Act (FIFRA) as amended (7 U.S.C.
136 et seq.). Before a product can be registered it must be shown that
it can be used without causing ``unreasonable adverse effects on the
environment'' (FIFRA section 3(c)(5), 7 U.S.C. 136a(c)(5)), that is,
without causing ``any unreasonable risk to man or the environment,
taking into account the economic, social, and environmental costs and
benefits of the use of the pesticide'' (FIFRA section 2(bb), 7 U.S.C.
136(bb)). The burden of proving that a pesticide meets this standard
for registration is, at all times, on the proponent of initial or
continued registration. If at any time the Agency determines that a
pesticide no longer meets this standard for registration, the
Administrator may cancel this registration under FIFRA section 6, 7
U.S.C. 136d.
The Special Review process provides a mechanism to permit public
participation in EPA's deliberations prior to issuance of any Notice of
Final Determination describing the regulatory action which the
Administrator has selected. The Special Review process, which was
previously called the Rebuttable Presumption Against Registration
(RPAR) process, is described in 40 CFR part 154, published in the
Federal Register of November 27, 1985 (50 FR 49015).
Prior to formal initiation of a Special Review, a preliminary
notification is sent to registrants and applicants for registration
pursuant to 40 CFR 154.21 announcing that the Agency is considering
commencing a Special Review.
If the Agency determines, after issuance of a preliminary
notification pursuant to 40 CFR 154.21, that it will not conduct a
Special Review, it is required under 40 CFR 154.23 to issue a proposed
decision to be published in the Federal Register. That regulation
requires that a period generally not less than 30 days be provided for
public comment on the Proposed Decision Not To Initiate a Special
Review. Subsequent to receipt and evaluation of comments on the
Proposed Decision Not To Initiate a Special Review, the Administrator
is required by 40 CFR 154.25 to publish in the Federal Register his/her
final decision regarding whether or not a Special Review will be
conducted.
B. Regulatory Background
Lindane (gamma-hexachlorocyclohexane) is a broad-spectrum
organochlorine insecticide/acaricide registered for control of insects
and other invertebrates on a wide variety of sites. Lindane is
currently used for agricultural crop seed treatments, livestock,
hardwood lumber/logs, pecans, commercial ornamentals, and a variety of
other sites including households and structures, forest trees, pets,
and assorted fruits and vegetables.
1. Special Review (1977-1983). The regulatory history of lindane
includes a full Special Review based on questions of carcinogenicity,
fetotoxicity/teratogenicity, reproductive effects, its potential to
cause blood dyscrasias, and acute toxicity to aquatic wildlife.
Previous Position Documents (PD) published on lindane include:
a. A PD-1 (which initiated a Special Review) in 1977, on the basis
of carcinogenicity, chronic reproductive and fetotoxic effects, and
acute effects on aquatic organisms.
b. A PD-2/3 (which provided a full discussion of hazards,
exposures, risks, benefits, regulatory options and a proposed
regulatory decision) in July 1980 proposed to cancel most of the uses
of lindane. The proposal was based on a risk/benefit determination
which suggested that the risks considerably outweighed the benefits
associated with lindane's continued use.
c. A PD-4 (final determination)/NOIC, published in the Federal
Register of October 19, 1983 (48 FR 48512), presented EPA's final
determination on lindane. It was based on a revised analysis of the
risks and benefits, following careful consideration of the comments EPA
had received from the Scientific Advisory Panel (SAP), the U.S.
Department of Agriculture, members of the affected industries, and the
general public. The decision described in the PD-4/NOIC was quite
different from the proposed decision in the PD-2/3. EPA originally
planned to cancel all of lindane's uses except for the commercial
ornamental, livestock, and dog wash uses. The final decision was to
continue registration of most uses of lindane. The Agency cancelled the
indoor uses of smoke fumigation devices and the use of dog dips to
control pests other than mites. All other uses were continued with
various restrictions. Those restrictions varied according to the degree
of hazard associated with the use, but typical requirements included
protective clothing, label statements describing necessary precautions,
and restrictions of some products to certified pesticide applicators.
The carcinogenic effect was not rebutted by information submitted
in response to the PD-4/NOIC. Following an Agency risk/benefit analysis
based on the carcinogenic risk, the registrations for lindane smoke
fumigation devices for indoor domestic use were phased out (with
cancellation becoming effective May 1986), and lindane dog dips for the
control of pests other than mites were cancelled. The dog dip
cancellation was challenged, and subsequently the dog dip use for pests
other than mites was permitted for commercial use (kennel, farm, and
sport dog uses only) provided additional precautions to limit
applicator exposure appeared on the labeling. The PD-4/NOIC stated
EPA's intent to restrict certain lindane products to Certified
Applicators or persons under their direct supervision. The restricted
uses include avocados, pecans, livestock sprays, forestry, Christmas
trees, commercial ornamentals, structural treatment, dog shampoos, and
dog dusts. The PD4/NOIC also stated EPA's intent to require the use of
protective clothing for applicators using lindane products for seed
treatment by manual means, livestock sprays, avocados, pecans,
forestry, Christmas trees, hardwood lumber, ornamentals, crawl space
treatments, dog dips, and dog shampoos.
2. Special Review Preliminary Notification (1985). Just prior to
publication of the PD-4, the Agency received from the registrants of
lindane a 90-day subchronic rat feeding study showing kidney effects.
In order to properly evaluate the study, a thorough review of the
complete subchronic and chronic data base was necessary. The Agency
decided not to delay issuance of the PD-4 until this review was
complete because it did not want to delay the implementation of the
regulatory measures outlined in the PD4. Pursuant to 40 CFR 154.21, on
September 18, 1985, EPA notified registrants and applicants for
registrations for lindane that it was considering initiating a new
Special Review based on the study results showing kidney effects. This
notification, which is the subject of today's notice, noted the
Agency's concern for workers who are exposed to lindane for the
forestry and uninhabited building uses. Registrants and applicants for
registration were given 30 days to comment on the Agency's proposal to
commence a Special Review for certain uses including forestry and
warehouses. Registrants requested and received a 3-week extension for
submitting comments.
Registrant rebuttal comments were submitted by Centre International
d'Etudes du Lindane (CIEL) on October 22, 1985. (CIEL represents all
lindane registrants holding U.S. registrations for the insecticide
lindane). These comments will be briefly addressed in Unit III. of this
notice. Furthermore, a Registration Standard was scheduled to be issued
which would include a complete review of lindane's general toxic
effects.
3. Registration Standard. A Registration Standard was published on
lindane in September 1985 (EPA RS-85-027) and reflected a reassessment
of the data base used in the Special Review for lindane as well as a
review of all other data available to the Agency, including the 90-day
subchronic rat feeding study.
Based on a comprehensive rereview of previous submissions and some
new data, the Agency determined that for most use sites, the benefits
of use of lindane exceeded the risks, so long as the precautions
mandated by the PD-4 were adhered to. As discussed above, potential
unacceptable risks to workers were calculated for spray uses for
forestry and warehouses (uninhabited buildings and empty storage bins)
based on irreversible kidney toxicity observed in the rat 90-day
feeding study.
4. Section 6(f) Notice. A notice, published in the Federal Register
of November 17, 1993 (58 FR 60630), pursuant to section 6(f)(1) of the
Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), announced
EPA's receipt of requests from a number of registrants to voluntarily
amend registrations of pesticide products containing lindane to delete
certain uses. The section 6(f) notice included one site (uninhabited
buildings) which is also a subject of today's notice.
II. Risk Concerns Underlying Preliminary Notification
A. Toxicity Concerns
The Registration Standard discussed the results of the subchronic
90-day feeding study in the rat which showed that lindane causes
adverse pathological effects (i.e., lesions), primarily in the kidney
of male rats, but also in the liver of male and female rats. Kidney
lesions were not completely reversed after allowing 6 weeks for
recovery on a lindane-free diet. No adverse effects on kidney structure
in fe2male rats were noted. Renal changes, which included tubular
degeneration, hyaline droplets, tubular casts, tubular distention,
interstitial nephritis, and basophilic tubules, were stated to be
irreversible with a no-observable-effect level (NOEL) of 4 parts per
million (ppm) in the diet equivalent to 0.3 milligram per kilogram of
body weight per day (mg/kg/day). Hepatocellular hypertrophy was noted
at the same lowest effect level (LEL) as the kidney lesions. The liver
toxicity results from the increased need to produce enzymes to detoxify
lindane and are considered a typical response and defensive mechanism
to the presence of foreign substances. The liver toxicity was not
regarded as a specific response to lindane.
B. Exposure
The September 18, 1985 preliminary notification to affected
registrants and applicants stated that the Agency's concerns were
limited to exposure from two uses: forestry and warehouse (uninhabited
buildings and empty storage bins). The Margins of Exposure (MOE) for
forestry applicator/mixer/loaders and for warehouse applicators were 11
and 20, respectively. MOE's for forestry applicator uses ranged from 20
to 90. Applicators, mixers, and loaders were assumed to follow
precautions on the registered labels current at that time. The
notification indicated that the Agency would consider all comments in
its determination of whether to initiate a Special Review of pesticide
products containing lindane. Since the issuance of the preliminary
notification, the Agency has determined that the kidney effects do not
meet the risk criteria for initiation of Special Review. Because EPA no
longer believes there is a kidney-related hazard posed to humans, a
discussion of exposure will not be presented. A more detailed
discussion of the exposure assessment used as a basis for the September
18, 1985 preliminary notification may be found in the Registration
Standard.
III. New Information
After the initial demonstration that lindane produces kidney
lesions, the Agency required and received 90-day subchronic inhalation
studies in rats (HED Document No.: 005059, April 25, 1986), and mice
(HED Document No.: 007304, June 30, 1989), dermal studies in rats (HED
Document No.: 007189, May 18, 1989) and rabbits (HED Document No.:
008610, September 27, 1991) and a chronic feeding/carcinogenicity study
in rats (HED Document Nos.: 007461, August 30, 1989 and 009909,
December 30, 1992). In summary, only studies in rats demonstrated the
occurrence of lesions in the kidneys, and only the males were affected.
There was no evidence that the kidneys of mice, rabbits, or female rats
were similarly affected. After publication of the Registration
Standard, the Agency received a 90-day rat subchronic inhalation study
with lindane which was written in German. Translations of this study
indicated a NOEL for the kidney changes of 0.1 mg/cubic meter. The
kidney lesions noted were transient in nature and were not noted in
rats after allowing 6 weeks for a recovery phase. The study results did
not demonstrate any signs of kidney dysfunction.
The chronic feeding/carcinogenicity study did not indicate any
evidence of lindane-induced kidney tumors or preneoplastic lesions.
However, the characteristic nonneoplastic lesions produced by a protein
(Alpha 2u-Globulin (2u-g)), found in the kidneys of male rats
which induces kidney effects were present. For example, one aspect of
this study included a chemical analysis of the kidney for increased
levels of the 2u-g protein. Clear and pronounced increases in
this protein were demonstrated in a dose-related manner (HED Document
No.: 007859, April 10, 1990). Independent industrial and academic
researchers had, a few years earlier, reported similar effects in the
male rat kidney due to responses to certain chlorinated hydrocarbons
and other chemicals. A pattern of effects emerged that indicated that
only the male rat kidney, but not the kidney of female rats or the male
and female kidneys of other species, was affected by this special group
of chemicals. This particular kidney lesion was ultimately demonstrated
to be linked to the potential for this special group of chemicals to
increase levels of 2u-g. This special group of chemicals
apparently bind the 2u-g in such a manner that it is not
excreted in the urine but accumulates in the kidney of male rats and
ultimately causes pathological lesions. For some, but not all,
2u-g binding chemicals, the pathological condition progresses
to neoplasia (kidney tumors). Thus, consistent with the chemical
structure of lindane, animal models and analytical chemistry, lindane
was demonstrated to be a classical example of an 2u-g-inducing
kidney pathogen in the male rat kidney.
The Agency published a document outlining the policy for risk
assessment for chemical agents that affect the male rat kidney through
the 2u-g mechanism (refer to document EPA/625/391/019F,
September 1991, Risk Assessment Forum Monograph entitled ``Alpha2u-
Globulin: Association with Chemically Induced Renal Toxicity and
Neoplasia in the Male Rat''). Consistent with this policy, chemicals
which cause lesions in the male rat kidney through the 2u-g
mechanism exclusively are not regulated on the basis for their
potential to cause kidney effects in male rats.
IV. Comments Received on Preliminary Notifications
The Centre Internationale d'Etudes du Lindane (CIEL), which
represents all the lindane registrants, commented in detail on the
Agency's preliminary notification. The main points of CIEL's comments
and the Agency's responses are summarized below.
CIEL Comment: CIEL challenged the Agency's claim that lindane
exposure produced irreversible renal effects in rats by pointing out
that the 90-day subchronic data show a trend toward reversibility of
renal effects; only the lack of a longer recovery period in the study
prevented a full reversibility of renal changes.
Agency Response: After reinspecting the pathology report and data
sheets, the Agency concurs with CIEL that the kidney pathology should
not be described as permanent or irreversible, but that the term
``slowly reversible'' more appropriately describes the effect. Although
some signs of pathology are evident after a 6-week recovery period, the
intensity or severity is much reduced and there is no tubular
degeneration, the lesion that was considered to be the most serious. In
addition, the Agency believes that the kidney effects were the result
of 2u-g and are specific to male rats and not found in other
species.
CIEL Comments: The MOE values should be increased by a factor of 5
to 10 because the rats in the 90-day study received oral administration
of lindane, whereas the lindane applicators for the uses in question
have mainly dermal exposure. CIEL commented that there is a 5- to 10-
fold lower acute toxicity after dermal exposure than after oral
administration.
Agency Response: The Agency's original review of existing studies
on lindane indicated that there were no adequate studies to assess
lindane toxicity through the dermal route of application. Therefore,
the Agency required that registrants perform additional studies to
clarify this point. A rat dermal toxicity study was submitted on May
18, 1989, and a rabbit dermal toxicity study on September 27, 1991.
These studies support the hypothesis that lindane induces a lesion
specific to the male rat kidney. The Agency will use the 90-day dermal
toxicity studies for future risk assessments.
CIEL Comment: Studies on humans, including occupational exposure,
revealed no kidney damage.
Agency Response: The Agency originally determined that the results
of the studies on human occupational exposure were inconclusive.
Although the studies reporting the results of human exposure did not
include specific kidney function tests, the available data indicate
that individuals potentially exposed to lindane did not develop overt
kidney functional changes. Although two studies showed decreases in
levels of blood creatinine and increases in reticulocytes and
polymorphonuclear leukocytes relative to controls, it is not conclusive
that these changes were the direct result of exposure to lindane per
se. However, the epidemiology studies have several weaknesses which
include a small number of subjects, failure to report the health status
of absentees at the time the blood samples were taken, and failure to
test for subtle changes in kidney functions. Also, pathological changes
in the kidney may occur in the absence of overt functional changes; the
studies designed could not assess this possibility. The Agency has no
evidence that human kidney function has been affected by lindane.
CIEL Comment: The Agency's estimates of applicator exposure are
inaccurate because: (1) For forestry uses, the estimates are based on a
surrogate study using grassland application (Lavy et al., 1980), rather
than forest trees; (2) the forestry use exposure figure should be 1.3
mg/hour with a dermal absorption of 5 percent; and (3) for warehouse
exposure, a study with aerosol application should be used instead of
the surrogate DDT fan-type spray study used by the Agency to estimate
exposure.
Agency Response: Regarding points (1) and (2), the Agency's
assessment for forestry use of lindane utilized three surrogate studies
in addition to the study by Lavy et al., in order to increase
replicates and minimize bias that could result from the selection of a
single surrogate study. The Lavy et al. study had a number of
weaknesses by Agency standards, including failure to specify the height
of application; brush application when backpack equipment was used;
failure to measure hand dermal exposure (often an appreciable part of
the total dermal exposure); and failure to measure exposure to the
legs.
The Agency's mean value of 5.3 milligrams per hour is considered
reasonable, given the degree of variability inherent in exposure
studies. The Agency is not aware of any dermal absorption study showing
5 percent dermal absorption and therefore assumed a dermal absorption
of 10 percent based on data on liquid formulations as described in the
preliminary determination (PD 2/3) of the earlier Special Review of
lindane. EPA still considers the 10 percent dermal absorption factor
appropriate. Risk assessments, however, should be based on the 90-day
dermal studies.
Regarding point (3) in which CIEL claims that a study using an
aerosol sprayer would be more appropriate for warehouse exposure
assessment, the Agency realizes that the aerosol characteristics are
partially dependent on the type of equipment used. However, there is no
evidence that a very fine spray is used for storage bin application; in
fact, the label of one registered product instructs the user to apply
the material as a coarse spray, not a fine aerosol as claimed by CIEL.
Therefore, after careful consideration of the CIEL's comments about
exposure, the Agency believes that the exposure estimate used to
calculate the MOE's were reasonable and appropriate for the forestry
and warehouse uses.
V. Agency's Decision Regarding Special Review
At this time, the Agency proposes not to initiate a Special Review
of pesticide products containing lindane based on the male rat kidney
effects. EPA has concluded that any renal lesions in male rats observed
in connection with 2u-g accumulation is a species-specific
effect that is not relevant to human risk assessment. The Agency agrees
that the evidence as provided in the 90-day subchronic rat study does
not raise as great a concern regarding lindane as originally suspected.
The available evidence does not establish a credible relationship
between lindane and potential renal effects in humans. In conclusion,
the Agency has determined that it is not appropriate to conduct a
Special Review of lindane based on male rat renal effects.
The Agency is reexamining its assessment of lindane's potential to
cause liver tumors in mice and developmental toxicity in rats. Lindane
is currently classified by the Office of Research and Development
Carcinogenicity Assessment Group (ORD CAG, July 23, 1985) as a ``B2-C''
(a probable-to- possible carcinogen) based on liver tumors primarily
from reports in the published literature. Based on these data CAG
provided a cancer potency Q1* of (1.1 mg/kg/day)-1 for risk
assessment. The Office of Pesticide Program's Health Effects Division
(HED) Reference Dose (RFD) Committee Peer Review met on July 8, 1993,
and determined that while the available mouse studies with lindane
provide some information, there are no mouse carcinogenicity studies
which meet current criteria for acceptability for regulatory purposes.
Thus, the reevaluation of lindane for carcinogenicity classification is
pending receipt and review of a new mouse carcinogenicity study to be
conducted under current guideline criteria which will be required in
the form of a Data Call In (DCI) to be published in the near future.
The committee also determined that a developmental neurotoxicity
study should be conducted to assess the effects of lindane on the
development of the nervous system as previous studies suggest that
lindane is able to cross the placenta and to be a neurotoxicant. This
data request will also be included in the above-mentioned DCI.
Upon receipt and review of the above studies, if such review
indicates any remaining concerns, EPA could initiate a Special Review
or take other appropriate regulatory action.
VI. Public Comment Opportunity and Public Docket
The Agency is providing a 60-day period to comment on this notice.
Comments must be submitted by May 17, 1994. All comments and
information should be submitted in triplicate to the address given in
this notice under ADDRESSES above. The comments and information should
bear the identifying notation OPP-30000/10H. After receipt and
evaluation of comments on this notice, the Agency will issue a final
decision in the Federal Register regarding whether or not a Special
Review will be conducted.
The Agency has established a public docket (OPP-30000/10H) for this
proposal for not initiating a Special Review of Lindane. This public
docket will include this notice, any other notices pertinent to the
Agency's decision regarding the Special Review of Lindane, non-CBI
documents and copies of written comments or other materials submitted
to the Agency in response to the pre-special review registrant
notifications and this notice regarding Special Review of Lindane, and
a current index of materials in the public docket.
List of Subjects
Environmental protection, Agricultural commodities, Pesticides and
pests.
Dated: March 4, 1994.
Victor J. Kimm,
Acting Assistant Administrator for Prevention, Pesticides and Toxic
Substances.
[FR Doc. 94-6280 Filed 3-17-94; 8:45 am]
BILLING CODE 6560-50-F