Lindane; Proposed Decision not to Initiate a Special Review

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]

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