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Lindane (Isotox) - Special Review Declined 7/95

ENVIRONMENTAL PROTECTION AGENCY
[OPP-30000/10I; FRL-4944-4]

Lindane: Decision Not To Initiate a Special Review on Kidney Effects

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

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SUMMARY: EPA (the Agency) announces its decision not to initiate a Special Review for pesticide products containing
lindane based on worker health concerns arising from studies showing irreversible renal effects in the rat. EPA has
determined that these effects occur only in the kidneys of the male rat and are not relevant for human risk assessment.
The Agency is currently developing a strategy to examine the role organochlorine chemicals, such as lindane, may play
as endocrine disrupters. Should the Agency determine that this or other effects cause unacceptable risk, it will take
appropriate regulatory action.

FOR FURTHER INFORMATION CONTACT: By mail, David H. Chen, Special Review and Reregistration Division (7508W), Office of
Pesticide Programs, Environmental Protection Agency, 401 M St., SW., Washington, DC 20460. Office location, telephone
number and e-mail address: Special Review Branch, Rm. WF32C6, Crystal Station #1, 2800 Crystal Drive, Arlington, VA.,
telephone Number: 703-308-8017, internet e-mail address: chen.david@epamail.epa.gov

SUPPLEMENTARY INFORMATION: On March 18, 1994, EPA announced its proposed decision (and solicitation for public comment)
not to initiate a Special Review of lindane for male rat kidney effects described in the September 18, 1985 preliminary
notification to lindane registrants and applicants. The Agency has reviewed the available data in light of the Agency's
1991 alpha2u-globulin (α2u-g) regulatory policy and the public comments received in response to the March, 1994
announcement. This notice provides the Agency's final decision, its response to comments, and the rationale for its
final decision.

I. Introduction

Background information on pesticide registration and the Special Review process can be found in the Federal
Insecticide, Fungicide and Rodenticide Act (FIFRA) as amended (7 U.S.C. 136 et seq.), and appropriate sections under 40
CFR part 154, published on November 27, 1985 (50 FR 49015). For a more comprehensive summary of the legal and
regulatory background pertaining to lindane, refer to the Agency's proposed decision not to initiate a Special Review
on rat kidney effects, published on March 18, 1994 (59 FR 12916). Below is a summary of the text of that document.

A. 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. This pesticide is currently registered for use on field
and vegetable crops (including seed treatments) and non-food crops (ornamental and tobacco), greenhouse food crops
(vegetables), forestry (including Christmas trees), domestic outdoor and indoor (pets and household uses), commercial
indoor (food/feed storage areas and containers), animal premises, wood or wooden structures, and human skin/clothing

(military use only).

B. Regulatory History

Between 1977 and 1983, EPA conducted a Special Review that was based on the carcinogenicity,
fetotoxicity/teratogenicity, and reproductive effects of lindane, and its potential to cause blood dyscrasia, as well
as acute toxicity to aquatic wildlife. In the Agency's final determination (PD-4) published in 1983, the Agency
canceled the indoor uses of smoke fumigation devices (by May, 1986) and the use of dips on dogs to control pests other
than mites. Subsequently, the dog dip use was permitted for commercial use (kennel, farm, and sport dog uses only),
provided that additional label

[[Page 38330]]
precautions were added to reduce applicator exposure. All other uses were allowed to continue 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.

Following the conclusion of the Special Review in 1983, the Agency received a new 90-day subchronic rat feeding study
which showed histopathological kidney and liver changes. Based on the effects observed in this study, on September 18,
1985, EPA notified registrants and applicants for registrations for lindane that the Agency was considering initiating
a new Special Review base on concerns for workers exposed to lindane as a result of its forestry and uninhabited
building uses.

The subchronic feeding study showed that lindane causes histopathological lesions, primarily in the kidney of male
rats, and also in the liver of male and female rats. The kidney lesions were not completely reversed after a 6-week
recovery period on a lindane-free diet. These renal changes included tubular degeneration, hyaline droplets, tubular
casts, tubular distention, interstitial nephritis, and basophilic tubules. No adverse effects on kidney structure in
female rats were noted. The liver effects (hepatocellular hypertrophy) were not regarded as a specific response to
lindane because they are related to increased detoxification processes, and are considered a typical response and
defensive mechanism to the presence of foreign substances.

Subsequent to the initial demonstration of lindane induced rat kidney lesions, the Agency required and received a
number of additional toxicological studies aimed at elucidating the observed kidney effects. In summary, only male rats
demonstrated the lindane induced kidney effects; while mice, rabbits and female rats did not. In the rat chronic
feeding/carcinogenicity study, male Wistar rats demonstrated the characteristic α2u-g kidney histopathological
sequence of kidney lesions associated with increased "accumulation of hyaline droplets containing
α2u-g", "necrosis of tubule epithelium" leading to tubular degeneration, and subsequent formation
of granular casts, without any evidence of lindane induced kidney tumors. (Refer to "Alpha2u-Globulin: Association
with Chemically Induced Renal Toxicity and Neoplasia in the Male Rat", Risk Assessment Forum Monograph
(EPA/625/391/019F, September 1991, page 2). The Monograph is available through the U.S. Government Printing Office:
1992-648-003/41809. A chemical analysis of the kidney for evidence of increased levels of α2u-g revealed clear
and pronounced compound dose-related increases in this protein. Furthermore, the exacerbation of hyaline droplets was
due to the apparent binding of the α2u-g to lindane as an adduct, which accumulates in the kidney proximal
tubules and cannot be excreted (refer to Monograph, page 92). Lindane is one of a group of α2u-g chemical
inducers tested that has been shown to produce "the sequence of lesions characteristic of the α2u-g
syndrome" in the absence of renal tubule tumors in the male Wistar rat (refer to Monograph, page 89).
In the above Monograph, the Agency outlined its regulatory policy for human risk assessment for chemical agents that
affect the male rat kidney through the α2u-g mechanism (refer to Monograph, page 89). This policy states "if
a compound induces alpha 2u-globulin accumulation in hyaline droplets, the associated nephropathy in male rats is not
an appropriate endpoint to determine noncancer (systemic) effects potentially occurring in humans. Likewise,
quantitative estimates of noncancer risk (e.g., reference doses and margin of exposure determinations) are based on
other endpoints." In the case of lindane, the Agency has reviewed the weight-of-evidence in light of the 1991
α2u-g policy, and has concluded that the observed renal effects were the result of the α2u-g mechanism. The
potential for lindane to induce kidney lesions in male rats is not currently regarded as being relevant to human health
risk assessment. Therefore, the renal effects observed do not provide a basis for a Special Review of lindane.

II. Comments Received on the Proposed Notice Not to Initiate a Special Review on Kidney Effects

In its March, 1994 proposal not to initiate a Special Review, the Agency provided a 60-day comment period, which ended
on May 17, 1994. EPA received five sets of comments, most of which were responses from public interest groups.
Comment. All of the commenters urged the Agency not to abandon the Special Review of lindane because there are
additional health concerns beyond kidney effects that are currently not under consideration in the review by EPA.
Agency Response. In 1983, EPA concluded a major Special Review effort of lindane based on carcinogenicity,
fetotoxicity/ teratogenicity, reproductive effects, and acute effects on aquatic organisms. This effort resulted in the
cancellation of indoor uses of smoke fumigation devices and greatly limited the use of pet dips on dogs. In addition,
there were uses that were allowed to continue only if certain imposed restrictions were implemented. The restrictions
were based on the degree of associated hazards, and included changes in warning labels, the wearing of protective
clothing, and restrictions to limit uses to certified pest control operators. Today's action only deals with the
concerns originally raised in the 1985 preliminary notification to registrants and applicants of lindane, that is,
kidney effects to workers exposed to lindane in forestry and uninhabited building uses. The Agency has concluded that
the unique kidney effects induced via the α2u-g mechanism in the rat have no direct biological relevance for
human risk assessment. Consequently, there is no basis for initiating a Special Review of lindane due to the kidney
effects at this time. However, the Agency recognizes that organochlorine pesticides, such as lindane, can cause

endocrine disruption that may be associated with risk concerns. The Agency is currently developing a strategy to look
at organochlorine pesticides as a group to examine their role as endocrine disrupters. Although the Agency is not
initiating a Special Review on lindane for kidney effects, the findings from a comprehensive examination of the group
of chemicals could lead to further regulatory action on lindane.

Comment. Several commenters pointed to concerns for breast cancer, neurotoxic, endocrine-disruption and other health
effects from the continued use of lindane products. The commenters urged that EPA take more aggressive actions to
further reduce risk.

Agency Response. The issues raised by the commenters were not Special Review triggers in the 1985 preliminary
notification letter to registrants of lindane. Also, the identification of a possible toxic response or health concern
to a given chemical does not always indicate that Special Review criteria have been exceeded. The recently completed
rat carcinogenicity study did not demonstrate an association between lindane exposure and carcinogenicity. Presently,
the Agency does not have a mouse carcinogenicity study that meets current acceptance criteria and a new study has been
requested. However, the literature reports suggesting an apparent relationship between lindane and breast cancer in
humans require further

[[Page 38331]]
evaluation. Investigation is underway at the National Cancer Institute to determine whether the association found in
these studies can be confirmed. The possible endocrine effects reported in the literature to date have not been evident
in those studies conducted in rats reviewed by the Agency, nor has immunotoxicity been indicated to be a critical
endpoint for lindane toxicity. The Agency is considering additional data requirements for reregistration, including a
neurotoxicity study, and the need for requiring special studies to assess both immunotoxicity and endocrine effects.
The Agency is currently developing a strategy for examining the role of organochlorine chemicals as endocrine
disrupters. Such an effort could result in the Agency pursuing further regulatory action against lindane. Today's
action only deals with the kidney effects and does not preclude the Agency from taking future regulatory action against
this chemical based on the risk concerns raised above.

Comment. Several commenters suggested EPA ban further use of lindane because the severity of the pesticide's
environmental and health concerns have already caused regulators in more than a dozen countries to ban or severely
restrict the use of this chemical.

Agency Response. EPA updates and reviews its scientific database on a routine basis for new evidence on chemicals which
may identify risk concerns. Any regulatory action must meet the scrutiny of sound science and be consistent with the
statutes and regulations governing pesticide registration and use. The Agency will exercise its authority to ban or
restrict the use of pesticides when such action is necessary to protect against unreasonable adverse effects.

III. Reregistration Activities

EPA is considering what additional toxicological data are necessary to support continued registration, which include
carcinogenicity and developmental neurotoxicity studies. Upon receipt and review of any of these studies, the Agency
could initiate a Special Review or take other appropriate regulatory action if risk concerns are raised.

IV. Conclusion

Today's notice announces the Agency's final decision that the lindane induced kidney effects observed in male rats are
not relevant for human risk assessment, nor do these effects meet the risk criteria for initiation of a Special Review.
Because EPA no longer believes there is a renal-related hazard posed to humans, the Agency will not initiate a Special
Review for this effect. The Agency is developing a strategy to look at the role of organochlorine pesticides, such as
lindane, may play as endocrine disrupters to better understand the risks from this group of chemicals. This action does
not preclude the Agency from taking action on this chemical in the future as new information on this or any other risk
concern becomes known.

Dated: July 19, 1995.

Lynn R. Goldman,

Assistant Administrator for Prevention, Pesticides and Toxic Substances.

[FR Doc. 95-18368 Filed 7-25-95; 8:45 am] BILLING CODE 6560-50-F