[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]


-----------------------------------------------------------------------


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.

-----------------------------------------------------------------------

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