[Federal Register Volume 60, Number 143 (Wednesday, July 26, 1995)]
[Notices]
[Pages 38329-38331]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-18368]



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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: 
[email protected]

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 (2u-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 2u-g kidney histopathological sequence 
of kidney lesions associated with increased ``accumulation of hyaline 
droplets containing 2u-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 2u-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 
2u-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 2u-g chemical 
inducers tested that has been shown to produce ``the sequence of 
lesions characteristic of the 2u-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 2u-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 2u-g policy, and has concluded that the observed 
renal effects were the result of the 2u-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 2u-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