44582 Federal Register / Vol. 62, No. 163 / Friday, August 22, 1997 / Rules and Regulations

IX. Public Docket

A record has been established for this

rulemaking under docket control

number [OPP–300537]. A public version

of this record, which does not include

any information claimed as CBI, is

available for inspection from 8:30 a.m.

to 4 p.m., Monday through Friday,

excluding legal holidays. The public

record is located in Room 1132 of the

Public Information and Records

Integrity Branch, Information Resources

and Services Division (7506C), Office of

Pesticide Programs, Environmental

Protection Agency, Crystal Mall #2,

1921 Jefferson Davis Highway,

Arlington, VA 22202. Electronic comments can be sent

directly to EPA at:

opp-docket@epamail.epa.gov

Electronic comments must be

submitted as an ASCII file avoiding the

use of special characters and any form

of encryption. The official record for this

rulemaking, as well as the public

version, as described above, is kept in

paper form. Accordingly, in the event

there are objections and hearing request,

EPA will transfer any copies of

objections and hearing requests received

electronically into printed, paper form

as they are received and will place the

paper copies in the official rulemaking

record. The official rulemaking record is

the paper record maintained at the

Virginia address in Addresses at the

beginning of this document.

X. Regulatory Assessment

Requirements

This final rule establishes an

exemption from the tolerance

requirement under FFDCA section

408(d) in response to a petition

submitted to the Agency. The Office of

Management and Budget (OMB) has

exempted these types of actions from

review under Executive Order 12866,

entitled Regulatory Planning and

Review (58 FR 51735, October 4, 1993).

This final rule does not contain any

information collections subject to OMB

approval under the Paperwork

Reduction Act (PRA), 44 U.S.C. 3501 et

seq., or impose any enforceable duty or

contain any unfunded mandate as

described under Title II of the Unfunded

Mandates Reform Act of 1995 (UMRA)

(Pub. L. 104–4). Nor does it require and

prior consultation as specified by

Executive Order 12875, entitiled

Enhancing the Intergovernmental

Partnership (58 FR 58093, October 28,

1993), or special considerations as

required by Executive Order 12898,

entitled Federal Actions to Address

Environmental Justice in Minority

Populations and Low-Income

Populations (59 FR 7629), February 16,

1994), or require OMB review in

accordance with Executive Order 13045,

entitled Protection of Children from

Environmental Health Risks and Safety

Risks (62 FR 19885, April 23, 1997). In additions, since tolerance

exemptions that are established on the

basis of a petition under FFDCA section

408(d), such as the exemption in this

final rule, do not require the issuance of

a proposed rule, the requirements of the

Regulatory Flexibility Act (RFA) (5

U.S.C. 601 et seq.) do not apply.

Nevertheless, the Agency previously

assessed whether establishing

tolerances, exemptions from tolerances,

raising tolerance levels or expanding

exemptions might adversely impact

small entities and concluded, as a

generic matter, that there is no adverse

economic impact. The factual basis for

the Agency’s generic certification for

tolerance actions published on May 4,

1981 (46 FR 24950), and was provided

to the Chief Counsel for Advocacy of the

Small Business Administration.

XI. Submission to Congress and the

General Accounting Office

Under 5 U.S.C. 801(a)(1)(A), as added

by the Small Business Regulatory

Enforcement Fairness Act of 1996, the

Agency has submitted a report

containing this rule and other required

information to the U.S. Senate, the U.S.

House of Representatives and the

Comptroller General of the General

Accounting Office prior to publication

of the rule in today’s Federal Register.

This is not a major rule as defined by

5 U.S.C. 804(2).

List of Subjects in 40 CFR Parts 180 and

186

Environmental protection,

Administrative practice and procedure,

Agricultural commodities, Animal

feeds, Pesticides and pests, Reporting

and recordkeeping requirements.

Dated: August 14, 1997.

Stephen L. Johnson,

Acting Director, Office of Pesticide Programs.

Therefore, 40 CFR part 180 is

amended as follows:

1. The authority citation for part 180

continues to read as follows:

Authority: 21 U.S.C. 346a and 371.

2. Section 180.1184 is added to

subpart D to read as follows:

§ 180.1184 Coat Protein of Watermelon

Mosaic Virus-2 and Zucchini Yellow Mosaic

Virus and the genetic material necessary for

its production; exemption from the

requirement of a tolerance.

An exemption fron the requirement of

a tolerance is established for residues of

the biological plant pesticide Coat

Protein of Watermelon Mosaic Virus-2

and Zucchini Yellow Mosaic Virus and

the genetic material necessary for its

production in or on all food

commodities.

[FR Doc. 97–22394 Filed 8-21-97; 8:45 am]

BILLING CODE 6560-50-P

ENVIRONMENTAL PROTECTION

AGENCY

40 CFR Parts 180 and 186

[OPP–300541; FRL–5739–7]

RIN 2070–AB78

Thiodicarb; Pesticide Tolerance

AGENCY: Environmental Protection

Agency (EPA).

ACTION: Final rule.

SUMMARY: This regulation establishes a

tolerance for combined residues of

thiodicarb and its metabolite methomyl

in or on broccoli, cabbage, cauliflower,

and leafy vegetables (except Brassica

vegetables). The petitioner, RhonePoulenc Ag Company, requested this

tolerance under the Federal Food, Drug

and Cosmetic Act (FFDCA), as amended

by the Food Quality Protection Act of

1996 (FQPA) (Pub. L. 104-170).

DATES: This regulation is effective

August 22, 1997. Objections and

requests for hearings must be received

by EPA on or before October 22, 1997.

ADDRESSES: Written objections and

hearing requests, identified by the

docket control number, [OPP–300541],

must be submitted to: Hearing Clerk

(1900), Environmental Protection

Agency, Rm. M3708, 401 M St., SW.,

Washington, DC 20460. Fees

accompanying objections and hearing

requests shall be labeled ‘‘Tolerance

Petition Fees’’ and forwarded to: EPA

Headquarters Accounting Operations

Branch, OPP (Tolerance Fees), P.O. Box

360277M, Pittsburgh, PA 15251. A copy

of any objections and hearing requests

filed with the Hearing Clerk identified

by the docket control number, [OPP–

300541], must also be submitted to:

Public Information and Records

Integrity Branch, Information Resources

and Services Division (7506C), Office of

Pesticide Programs, Environmental

Protection Agency, 401 M St., SW.,

Washington, DC 20460. If you wish to

submit in person, bring a copy of

objections and hearing requests to Rm.

1132, CM #2, 1921 Jefferson Davis Hwy.,

Arlington, VA.

A copy of objections and hearing

requests filed with the Hearing Clerk

may also be submitted electronically by
Federal Register / Vol. 62, No. 163 / Friday, August 22, 1997 / Rules and Regulations 44583

sending electronic mail (e-mail) to: oppdocket@epamail.epa.gov. Copies of

objections and hearing requests must be

submitted as an ASCII file avoiding the

use of special characters and any form

of encryption. Copies of objections and

hearing requests will also be accepted

on disks in WordPerfect 5.1 file format

or ASCII file format. All copies of

objections and hearing requests in

electronic form must be identified by

the docket control number [OPP–

300541]. No Confidential Business

Information (CBI) should be submitted

through e-mail. Electronic copies of

objections and hearing requests on this

rule may be filed online at many Federal

Depository Libraries.

FOR FURTHER INFORMATION CONTACT: By

mail: Thomas C. Harris, Registration

Division 7505C, Office of Pesticide

Programs, Environmental Protection

Agency, 401 M St., SW., Washington,

DC 20460. Office location, telephone

number, and e-mail address: Crystal

Mall #2, 1921 Jefferson Davis Hwy.,

Arlington, VA, (703) 305-5404, e-mail:

harris.thomas@epamail.epa.gov.

SUPPLEMENTARY INFORMATION: In the

Federal Register of March 5, 1997 (62

FR 10050)(FRL–5586–1) EPA issued a

notice pursuant to section 408 of the

Federal Food, Drug, and Cosmetic Act

(FFDCA), 21 U.S.C. 346a(e) announcing

the filing of a pesticide petition (PP) for

tolerance by Rhone-Poulenc Ag

Company, P.O. Box 12014, 2 T. W.

Alexander Drive, Research Triangle

Park, NC 27709. There were no

comments received in response to the

notice of filing.

The petition requested that 40 CFR

180.407 be amended by establishing a

tolerance for combined residues of the

insecticide thiodicarb (CAS number

59669-26-0, EPA chemical number

114501) and its metabolite methomyl

(CAS number 16752-77-5, EPA chemical

number 090301), in or on broccoli at 7

parts per million (ppm), cabbage at 7

ppm, cauliflower at 7 ppm , and leafy

vegetables (except Brassica vegetables)

at 35 ppm.

I. Risk Assessment and Statutory

Findings

New section 408(b)(2)(A)(i) of the

FFDCA allows EPA to establish a

tolerance (the legal limit for a pesticide

chemical residue in or on a food) only

if EPA determines that the tolerance is

‘‘safe.’’ Section 408(b)(2)(A)(ii) defines

‘‘safe’’ to mean that ‘‘there is a

reasonable certainty that no harm will

result from aggregate exposure to the

pesticide chemical residue, including

all anticipated dietary exposures and all

other exposures for which there is

reliable information.’’ This includes

exposure through drinking water and in

residential settings, but does not include

occupational exposure. Section

408(b)(2)(C) requires EPA to give special

consideration to exposure of infants and

children to the pesticide chemical

residue in establishing a tolerance and

to ‘‘ensure that there is a reasonable

certainty that no harm will result to

infants and children from aggregate

exposure to the pesticide chemical

residue. . . .’’

EPA performs a number of analyses to

determine the risks from aggregate

exposure to pesticide residues. First,

EPA determines the toxicity of

pesticides based primarily on

toxicological studies using laboratory

animals. These studies address many

adverse health effects, including (but

not limited to) reproductive effects,

developmental toxicity, toxicity to the

nervous system, and carcinogenicity.

Second, EPA examines exposure to the

pesticide through the diet (e.g., food and

drinking water) and through exposures

that occur as a result of pesticide use in

residential settings.

A. Toxicity

1. Threshold and non-threshold effect.

For many animal studies, a dose

response relationship can be

determined, which provides a dose that

causes adverse effects (threshold effects)

and doses causing no observed effects

(the ‘‘no-observed effect level’’ or

‘‘NOEL’’).

Once a study has been evaluated and

the observed effects have been

determined to be threshold effects, EPA

generally divides the NOEL from the

study with the lowest NOEL by an

uncertainty factor (usually 100 or more)

to determine the Reference Dose (RfD).

The RfD is a level at or below which

daily aggregate exposure over a lifetime

will not pose appreciable risks to

human health. An uncertainty factor

(sometimes called a ‘‘safety factor’’) of

100 is commonly used since it is

assumed that people may be up to 10

times more sensitive to pesticides than

the test animals, and that one person or

subgroup of the population (such as

infants and children) could be up to 10

times more sensitive to a pesticide than

another. In addition, EPA assesses the

potential risks to infants and children

based on the weight of the evidence of

the toxicology studies and determines

whether an additional uncertainty factor

is warranted. Thus, an aggregate daily

exposure to a pesticide residue at or

below the RfD (expressed as 100 percent

or less of the RfD) is generally

considered acceptable by EPA. EPA

generally uses the RfD to evaluate the

chronic risks posed by pesticide

exposure. For shorter term risks, EPA

calculates a margin of exposure (MOE)

by dividing the estimated human

exposure into the NOEL from the

appropriate animal study. Commonly,

EPA finds MOEs lower than 100 to be

unacceptable. This 100-fold MOE is

based on the same rationale as the 100-

fold uncertainty factor.

Lifetime feeding studies in two

species of laboratory animals are

conducted to screen pesticides for

cancer effects. When evidence of

increased cancer is noted in these

studies, the Agency conducts a weight

of the evidence review of all relevant

toxicological data including short-term

and mutagenicity studies and structure

activity relationship. Once a pesticide

has been classified as a potential human

carcinogen, the appropriate risk

assessment (e.g., linear low dose

extrapolations or MOE calculation based

on the appropriate NOEL) will be

carried out based on the nature of the

carcinogenic response and the Agency’s

knowledge of its mode of action.

2. Differences in toxic effect due to

exposure duration. The toxicological

effects of a pesticide can vary with

different exposure durations. EPA

considers the entire toxicity data base,

and based on the effects seen for

different durations and routes of

exposure, determines which risk

assessments should be done to assure

that the public is adequately protected

from any pesticide exposure scenario.

Both short and long durations of

exposure are always considered.

Typically, risk assessments include

‘‘acute’’, ‘‘short-term’’, ‘‘intermediate

term’’, and ‘‘chronic’’ risks. These

assessments are defined by the Agency

as follows.

Acute risk, by the Agency’s definition,

results from 1-day consumption of food

and water, and reflects toxicity which

could be expressed following a single

oral exposure to the pesticide residues.

High end exposure to food and water

residues are typically assumed.

Short-term risk results from exposure

to the pesticide for a period of 1-7 days,

and therefore overlaps with the acute

risk assessment. Historically, this risk

assessment was intended to address

primarily dermal and inhalation

exposure which could result, for

example, from residential pesticide

applications. Since enaction of FQPA,

this assessment has been expanded. The

assessment will only be performed

when there are primary dermal and

inhalation exposures that result from

residential exposures lasting from 1-7

days. However, the analysis will now

address both dietary and non-dietary
44584 Federal Register / Vol. 62, No. 163 / Friday, August 22, 1997 / Rules and Regulations

sources of exposure, and will typically

consider exposure from food, water, and

residential uses when reliable data are

available. In a short term assessment,

risks from average food and water

exposure, and high-end residential

exposure, are aggregated. High-end

exposures from all 3 sources are not

typically added because of the very low

probability of this occurring in most

cases, and because the other

conservative assumptions built into the

assessment assure adequate protection

of public health. However, for cases in

which high-end exposure can

reasonably be expected from multiple

sources (e.g. frequent and widespread

homeowner use in a specific

geographical area), multiple high-end

risks will be aggregated and presented

as part of the comprehensive risk

assessment/characterization. Since the

toxicological endpoint considered in

this assessment reflects exposure over a

period of at least 7 days, an additional

degree of conservatism is built into the

assessment; i.e., the risk assessment

nominally covers 1-7 days exposure,

and the toxicological endpoint/NOEL is

selected to be adequate for at least 7

days of exposure. (Toxicity results at

lower levels when the dosing duration

is increased.)

Intermediate-term risk results from

exposure for 7 days to several months.

This assessment is handled in a manner

similar to the short-term risk

assessment.

Chronic risk assessment describes risk

which could result from several months

to a lifetime of exposure. For this

assessment, risks are aggregated

considering average exposure from all

sources for representative population

subgroups including infants and

children.

B. Aggregate Exposure

In examining aggregate exposure,

FFDCA section 408 requires that EPA

take into account available and reliable

information concerning exposure from

the pesticide residue in the food in

question, residues in other foods for

which there are tolerances, residues in

groundwater or surface water that is

consumed as drinking water, and other

non-occupational exposures through

pesticide use in gardens, lawns, or

buildings (residential and other indoor

uses). Dietary exposure to residues of a

pesticide in a food commodity are

estimated by multiplying the average

daily consumption of the food forms of

that commodity by the tolerance level or

the anticipated pesticide residue level.

The Theoretical Maximum Residue

Contribution (TMRC) is an estimate of

the level of residues consumed daily if

each food item contained pesticide

residues equal to the tolerance. In

evaluating food exposures, EPA takes

into account varying consumption

patterns of major identifiable subgroups

of consumers, including infants and

children. The TMRC is a ‘‘worst case’’

estimate since it is based on the

assumptions that food contains

pesticide residues at the tolerance level

and that 100% of the crop is treated by

pesticides that have established

tolerances. If the TMRC exceeds the RfD

or poses a lifetime cancer risk that is

greater than approximately one in a

million, EPA attempts to derive a more

accurate exposure estimate for the

pesticide by evaluating additional types

of information (anticipated residue data

and/or percent of crop treated data)

which show, generally, that pesticide

residues in most foods when they are

eaten are well below established

tolerances.

Percent of crop treated estimates for

thiodicarb used in this tolerance

assessment are derived from federal and

private market survey data. EPA

considers these data reliable. A range of

estimates are supplied by this data and

the upper end of this range is used for

the exposure assessment. By using this

upper end estimate of percent of crop

treated, the Agency is reasonably certain

that exposure is not understated for any

significant subpopulation. Further,

regional consumption information is

taken into account through EPA’s

computer-based model for evaluating

the exposure of significant

subpopulations, including several

regional groups, to pesticide residues.

Review of this regional data allows EPA

to be reasonably certain that no regional

population is exposed to residue levels

higher than those estimated by the

Agency. To provide for the periodic

evaluation of these estimates of percent

crop treated, EPA will issue a data callin under section 408(f) to all thiodicarb

registrants for data on percent crop

treated. That data call-in will require

such data to be submitted every 5 years

as long as the tolerances remain in force.

For this pesticide, the most highly

exposed population subgroup (nonnursing infants <1 year old) for the

methomyl aggregate chronic assessment

was not regionally based.

Section 408(b)(2)(E) of the FFDCA

allows the Agency to rely on anticipated

or actual residue levels in establishing

a tolerance, provided that the Agency

requires that data be provided 5 years

after the establishment of the tolerance,

and thereafter as the Agency deems

appropriate, demonstrating that the

residue levels are not above the levels

relied upon. In establishing these

tolerances for thiodicarb, the Agency

relied upon Monte Carlo simulations

which relied upon anticipated or actual

residue levels. In addition, one of the

chronic assessments performed by

Novigen also utilized anticipated or

actual residue levels. Accordingly, the

Agency will require the submission of

data pursuant to section 408(f)(1) of the

FFDCA so that the Agency can

determine 5 years from the date these

tolerances are established whether

thiodicarb residues on food are below

the levels relied upon in establishing

these tolerances.

II. Aggregate Risk Assessment and

Determination of Safety

Consistent with section 408(b)(2)(D),

EPA has reviewed the available

scientific data and other relevant

information in support of this action,

EPA has sufficient data to assess the

hazards of thiodicarb and its metabolite

methomyl and to make a determination

on aggregate exposure, consistent with

section 408(b)(2), for a tolerance for

combined residues of thiodicarb and its

metabolite methomyl on broccoli at 7

ppm, cabbage at 7 ppm, cauliflower at

7 ppm, and leafy vegetables (except

Brassica vegetables) at 35 ppm. EPA’s

assessment of the dietary exposures and

risks associated with establishing the

tolerance follows.

Chemically, each thiodicarb molecule

is made up of two methomyl molecules

joined by a sulfur atom. Plant

metabolism studies show that thiodicarb

is metabolized to methomyl, methomyl

oxime, acetonitrile, and carbon dioxide.

A ruminant animal metabolism study

shows that thiodicarb is metabolized in

steps to methomyl, methomyl oxime,

acetonitrile, acetamide, acetic acid, and

carbon dioxide. The breakdown to

methomyl occurs more rapidly in plants

and the environment than in animals.

EPA has determined that residues of

acetamide, acetonitrile, methomyl

oxime, acetic acid, and carbon dioxide

resulting from the application of

thiodicarb or methomyl are not residues

of concern in animals and will not be

regulated. The only residues of concern

in plants and animals are thiodicarb and

its primary metabolite methomyl.

However, methomyl residues may result

from the application of either thiodicarb

or methomyl products. The following

discussion addresses:

1. The toxicological properties of

thiodicarb.

2. The toxicological properties of

methomyl.

3. A food exposure and risk analysis

for thiodicarb.
Federal Register / Vol. 62, No. 163 / Friday, August 22, 1997 / Rules and Regulations 44585

4. A drinking water exposure and risk

analysis for methomyl (resulting from

use of either thiodicarb or methomyl).

5. An aggregate (i.e. food + drinking

water) exposure and risk analysis for

methomyl (resulting from use of either

thiodicarb or methomyl).

There are no registered non-dietary

(residential or non-occupational) uses of

thiodicarb. Therefore, there is no nondietary exposure or risk associated with

thiodicarb.

A. Toxicological Profile

EPA has evaluated the available

toxicity data and considered its validity,

completeness, and reliability as well as

the relationship of the results of the

studies to human risk. EPA has also

considered available information

concerning the variability of the

sensitivities of major identifiable

subgroups of consumers, including

infants and children. The nature of the

toxic effects caused by thiodicarb and

its metabolite methomyl are discussed

below.

1. Toxicological profile of technical

thiodicarb— i. Acute toxicity. In several

acute oral toxicity studies with rats, the

LD50 ranged from 46.5 mg/kg for males

and 39.1 mg/kg for females, which is

Toxicity Category I, to 398 mg/kg for

males and 248 mg/kg for females, which

is Toxicity Category II (MRID 00025791,

00115604, 00115607). In a mouse study,

the LD50 was 73 mg/kg in males and 79

mg/kg in females (MRID 43784501).

The LD50 in an acute dermal toxicity

study with rabbits was found to be

greater than 2,000 mg/kg. This is

Toxicity Category III (MRID 44025501).

In an acute inhalation toxicity study

with rats, the LC50 for males was 0.126

mg/L, for females 0.115 mg/L, and

greater than 0.32 mg/L for dust. These

results are all considered to be in

Toxicity Category II (MRIDs 00041432

and 00045467.

Thiodicarb is a Toxicity Category III

primary eye irritant in rabbits.

Instillation resulted in slight irritation

(MRID 44025502).

Thiodicarb is a Toxicity Category IV

primary dermal irritant in rabbits (MRID

44025503) and thiodicarb induced a

weak dermal sensitization reaction in

guinea pigs (MRIDs 41891004 and

43373201).

An acute delayed neurotoxicity study

with thiodicarb in atropine-pretreated

hens, using a dose level of 660 mg/kg

(LD50) was negative (MRIDs 00044961

and 00053253). No data are available on

the acute and subchronic neurotoxicity

of thiodicarb.

ii. Subchronic toxicity. In a

subchronic toxicity study, Fisher 344

(COBS CD F/Crl BR) rats, 10/sex/group,

were administered thiodicarb (97% a.i.)

via the diet at dose levels of 1, 3, 10, and

30 mg/kg/day for 13 weeks. The NOEL

was 3 mg/kg/day, and the Lowest

Observed Effect Level (LOEL) was 10

mg/kg/day, based on decreased bodyweight gain, decreased red blood cell

(RBC) cholinesterase activity, and

decreased hemoglobin (MRID

00044965).

In a subchronic feeding study in

Beagle dogs, thiodicarb was

administered via the diet at dose levels

of 0, 15, 45, and 90 mg/kg/day for 13

weeks. The high dose was lowered to 76

mg/kg/day in females after day 36 due

to the deaths of 2 high-dose females.

The NOEL was 15 mg/kg/day, and the

LOEL was 45 mg/kg/day, based on

decreased RBC parameters (RBCs,

hematocrit and hemoglobin) in both

sexes (MRID 00044966).

In another subchronic toxicity study

in dogs, thiodicarb was administered via

the diet at dose levels of 0, 5, 15, and

45 mg/kg/day for 6 months. The NOEL

was 15 mg/kg/day, and the LOEL was 45

mg/kg/day, based on liver effects of

increased SGPT and increased liver

weight (MRID 00079474).

In a 21-day dermal toxicity study,

New Zealand White rabbits were

administered thiodicarb via the skin at

dose levels of 1,000, 2,000, and 4,000

mg/kg/day for 6 hours a day, 5 days a

week for 3 weeks. The NOEL was 1,000

mg/kg/day, and the LOEL was 2,000 mg/

kg/day, based on macrocytic anemia,

erythema, and edema (MRIDs 00043737

and 00044967).

In a 16-day dermal toxicity study,

New Zealand white rabbits were

administered thiodicarb via the skin at

dose levels of 1,000 and 4,000 mg/kg for

6 hours a day, 5 days a week for 3

consecutive weeks. The NOEL was

1,000 mg/kg/day, and the LOEL was

4,000 mg/kg/day, based on decreased

erythrocytes, decreased hemoglobin,

and decreased body weight (MRID

00043738).

In a 9-day dust inhalation study,

Sprague-Dawley rats were administered

thiodicarb particulates via the

inhalation route at dose levels of 0, 4.8,

17.7, and 59.5 mg/m3 for males, and 0,

4.8, 19.6, and 54.0 mg/m3 for females

(mean measured atmospheric

concentrations) for 6 hours a day for 9

days. The NOEL was not determined. At

4.8 mg/m3, two clinical signs typically

associated with cholinesterase effects

(pinpoint pupils and tremors) were

observed in both sexes. There were no

significant body-weight effects at this

dose level in either sex, and no

statistically significant effects were

observed in any cholinesterase

measurement (plasma, RBC, and brain)

at 4.8 or 17.7/19.6 mg/m3 in either sex

(MRIDs 00045467 and 00053252).

In a 4-week feeding study, CD-1 mice

of both sexes were administered

thiodicarb via the diet at dose levels of;

males 0, 6.2, 346, 734, and 1538 mg/kg/

day, females 0, 8.3, 491, 954, and 2030

mg/kg/day for 4 weeks. The NOEL was

6.2 and 8.3 mg/kg/day for males and

females respectively. The LOEL was 346

and 491 mg/kg/day for males and

females respectively. These results are

based on increased liver weight in

females and increased spleen weight in

both sexes (MRID 43611701).

In a subchronic feeding study, male

and female Fischer 344 rats were

administered thiodicarb via the diet at

dose levels of 0, 1, 3, 10, and 30 mg/kg/

day for 28 days. The NOEL for effects

on cholinesterase activity was 10 mg/kg/

day, and the LOEL was 30 mg/kg/day,

based on decreased plasma and RBC

cholinesterase activity (MRID

00098292).

iii. Chronic toxicity and

carcinogenicity. Beagle dogs were

administered technical thiodicarb via

the diet at dose levels of 0, 164 (male

4.4/female 4.5 mg/kg/day), 487 (male

12.8/female 13.8 mg/kg/day), and 1506

(male 38.3/female 39.5 mg/kg/day) ppm

for one year. The NOEL is male 4.4/

female 4.5 mg/kg/day, and the LOEL is

male 12.8/female 13.8 mg/kg/day, based

on cholinesterase inhibition. The

systemic NOEL is male 12.8/female 13.8

mg/kg/day and the systemic LOEL is

male 38.3/female 39.5 mg/kg/day, based

on reduced hematology parameters

including erythrocytes, hemoglobin, and

hematocrit (MRID 00159813).

In a chronic toxicity/carcinogenicity

study, Sprague-Dawley rats of both

sexes were administered thiodicarb via

the diet at dose levels of 0 ppm, 60 ppm

(male 3.3/female 4.5 mg/kg/day), 200

ppm (male 12/female 15 mg/kg), and

900 ppm (male 60/female 80 mg/kg) for

104 weeks. The systemic NOEL was 60

ppm (male 3.3/female 4.5 mg/kg/day)

and the LOEL was 200 ppm (male 12/

female 15 mg/kg/day), based on the

increased incidence of extramedullary

hemopoiesis in males and decreased

RBC cholinesterase in females. There

were no compound-related tumors

observed in the females. The high-dose

males displayed an increased incidence

of interstitial cell tumors in the testes

compared to the concurrent control

males, and the incidence was greater

than the historical control also (MRIDs

43308201, 43405001, 43596401).

In a carcinogenicity study, Charles

River CD-1 mice of both sexes were

administered thiodicarb via the diet at

dose levels of 0, 5, 70, and 1,000 mg/kg/

day for 97 weeks. The NOEL was 70 mg/
44586 Federal Register / Vol. 62, No. 163 / Friday, August 22, 1997 / Rules and Regulations

kg/day, and the LOEL was 1,000 mg/kg/

day, based on increased mortality in

females, decreased body-weight gain in

males, decreased hemoglobin,

hematocrit, and erythrocytes, increased

alanine aminotransferase and total

bilirubin, increased liver and spleen

weights, and increased incidences of

kidney, liver, and spleen lesions. In this

study, the administration of thiodicarb

in the diet to CD-1 mice resulted in

increased incidences of hepatocellular

tumors in both sexes. In both male and

female mice, there were statistically

significant increases in hepatocellular

adenomas, carcinomas and combined

adenomas/carcinomas at the highest

dose (1,000 mg/kg/day); there were also

statistically significant positive doserelated trends for adenomas and

carcinomas, alone and combined. The

incidence of adenomas and carcinomas

at the highest dose exceeded that of

historical controls in both sexes; in

addition, in male mice, the incidence of

adenomas at the mid-dose (70 mg/kg/

day) exceeded that of historical controls

(MRIDs 43000501 and 43619301).

In another carcinogenicity study,

Charles River CH:COBS CD-L (ICR)BR

mice of both sexes were administered

thiodicarb via the diet at dose levels of

1, 3, and 10 mg/kg/day for 104 weeks.

The NOEL was 3 mg/kg/day, and the

LOEL was 10 mg/kg/day, based on

mortality to thiodicarb in females (MRID

00041407).

Thiodicarb is classified as a B2 -

probable human carcinogen by the

Cancer Peer Review Committee (CPRC).

The B2 classification was based on

statistically significant increases in

hepatocellular adenomas, carcinomas,

and combined adenoma/carcinoma in

both sexes of the CD-1 mouse and

statistically significant increases in

testicular interstitial cell tumors in male

Sprague-Dawley rats.

iv. Developmental toxicity. In a rat

developmental toxicity study, pregnant

Charles River CD COBS rats were

administered thiodicarb via gavage on

gestation days 6-19 at dose levels of 0

(vehicle 0.5% methocel), 10, 20, and 30

mg thiodicarb/kg body weight/day. In

another rat developmental toxicity

study, pregnant Fisher 344 rats were

dosed via the diet on (a) gestation days

6 to 15 or (b) gestation days 0-20 at dose

levels of 0.5, 1.0, 3.0, and 100 mg

thiodicarb (>99%)/kg body weight/day.

When these two studies are considered

together, the maternal toxicity NOEL is

10 mg/kg/day, and the maternal toxicity

LOEL is 20 mg/kg/day, based on clinical

signs (tremors, inactivity). The

developmental toxicity NOEL is 3 mg/

kg/day, and the LOEL is 10 mg/kg/day,

based on decreased fetal body weights

and increased incidence of litters and

fetuses with developmental variations

which included unossification of

sternebrae #5 and/or #6 and other

sternebrae (MRIDs 00043739, 00043740,

00043741, 00053254, 00053255,

00053256).

In a developmental toxicity study,

artificially-inseminated New Zealand

white rabbits were administered

thiodicarb via gavage on gestation days

6 through 19 at dose levels of 0 (vehicle,

0.5% aqueous methylcellulose), 5, 20,

and 40 mg/kg/day. The maternal

toxicity NOEL was 20 mg/kg/day, and

the maternal toxicity LOEL was 40 mg/

kg/day, based on reduced body-weight

gain and food consumption. The

developmental toxicity NOEL was 40

mg/kg/day, the highest dose tested

(MRIDs 00159814, 40280001).

In a developmental toxicity study,

Charles River CD-1 mice were

administered thiodicarb on gestation

days 6 through 16 via gavage at dose

levels of 0 (vehicle 0.5% methocel), 50,

100, and 200 mg Thiodicarb/kg body

weight/day. The maternal toxicity NOEL

was 100 mg/kg/day, and the maternal

toxicity LOEL was 200 mg/kg/day,

based on increased mortality. The

developmental toxicity NOEL was 200

mg/kg/day, the highest dose tested

(MRIDs 00043742, 00043743, 00053257,

00053258).

v. Reproductive toxicity. In a twogeneration reproduction study, Crl:CD

BR/VAF/Plus rats were fed doses of 0,

5, 15, and 45 mg/kg/day of thiodicarb.

The reproductive/developmental

toxicity NOEL is 5 mg/kg/day, and the

reproductive/developmental toxicity

LOEL is 15 mg/kg/day, based on

decreased fetal body weight and

viability. The systemic NOEL is 5 mg/

kg/day and the systemic LOEL is 15 mg/

kg/day, based on decreased body

weight/gain and food consumption in

both sexes (MRIDs 42381301, 42381302,

42735101).

vi. Mutagenicity. Thiodicarb did not

induce a mutagenic response in the

Ames assay, with or without metabolic

activation (MRIDs 00044872, 00135792).

Thiodicarb induced dose-related

increased mutant frequencies in mouse

lymphoma TK +/¥ cells, with and

without metabolic activation and is

considered to have an equivocal weak

effect in the mouse lymphoma forward

mutation assay (MRID 00151574).

Thiodicarb, with or without metabolic

activation, did not cause a clastogenic

response in the chromosomes of

Chinese hamster ovary cells (MRID

00151572). Thiodicarb is considered

inactive in the primary rat hepatocyte

unscheduled DNA synthesis assay

(MRID 00151573).

2. Toxicological profile of technical

methomyl— i. Acute toxicity. The acute

oral LD50 values for methomyl with rats

were 34 and 30 mg/kg in males and

females, respectively (Toxicity Category

I). Clinical signs observed in all

treatment groups of both sexes included

tremors, low posture and salivation

(MRID 42140101).

The dermal LD50 value for methomyl

in rabbits was greater than 2000 mg/kg

(Toxicity Category III) for both sexes

(MRID 42074602).

The acute inhalation LC50 for

methomyl was 0.258 mg/L in rats for

both sexes (Toxicity Category II), based

on a four-hour exposure (nose only) to

technical grade methomyl aerosol

(MRID 42140102).

Methomyl is highly toxic via ocular

exposure. In a primary eye irritation

study, a female rabbit treated with 15

mg of technical methomyl (92.4%) died

20 minutes after the treatment with

typical cholinergic symptoms indicative

of neurotoxicity. Animals treated with

10 mg of methomyl exhibited similar

clinical signs of neurotoxicity but

survived. At this dose, corneal opacity

and iritis were observed at 1 hour after

the treatment and completely reversed

by 7 days (MRID 41964001).

Another primary eye irritation study

in rabbits using 30.5% methomyl

formulation showed corneal opacity and

conjunctivitis from 7 to 14 days in

washed and unwashed eyes,

respectively. Primary eye irritation for

methomyl was considered to be in the

Toxicity Category I (MRID 00053407).

A primary dermal irritation study

with technical methomyl in rabbits

showed no erythema or edema placing

methomyl in Toxicity Category IV

(MRID 42074603).

A dermal sensitization study in

guinea pigs using technical methomyl

showed that the compound is not a skin

sensitizer (MRID 42074605).

ii. Subchronic toxicity. In a 90-day

feeding study in rats, Charles River CD

rats (10/sex/group) were fed methomyl

at dietary levels of 0, 10, 50 and 250

ppm (equivalent to 0, 0.5, 2.5 and 12.5

mg/kg/day, respectively, based on the

standard conversion ratio) for 13 weeks.

An additional group received 125 ppm

(6.25 mg/kg/day) of the test material for

6 weeks and 500 ppm (25 mg/kg/day)

for the remaining 7 weeks. Treatment

did not cause increased mortalities. No

inhibition of cholinesterase activity was

observed in any treated group. The

NOEL is 125 ppm (6.25 mg/kg/day) and

the LOEL is 250 ppm (12.5 mg/kg/day)

based on inhibited body weight gain in

both sexes and erythroid hyperplasia in

the bone marrow of males (MRID

00007190).
Federal Register / Vol. 62, No. 163 / Friday, August 22, 1997 / Rules and Regulations 44587

In a 21-day dermal toxicity study,

New Zealand White rabbits were

dermally exposed to methomyl (98.35%,

a.i.) for 21 days at dose levels of 0, 5,

50 or 500 mg/kg/day. Clinical signs

included hyperactivity (increased

reaction to stimuli-noise) at the highdose (both sexes). At Day 21, mid- and

high-dose males and high-dose females

displayed significantly lower plasma

cholinesterase (ChE) activity. Mean RBC

ChE activity was also decreased, but

only slightly, at the high-dose (both

sexes). Brain ChE activity was

significantly decreased at the high-dose

(both sexes). At the mid-dose, although

not statistically significant, inhibition of

brain ChE activity was indicated (3/5

males and 4/5 females exhibited brain

ChE inhibition when compared with

controls). The NOEL for systemic

toxicity is 5 mg/kg/day and the LOEL is

50 mg/kg/day based on brain and

plasma ChE inhibitions. No dermal

irritation was observed (MRID

41251501).

iii. Chronic toxicity and

carcinogenicity. Sufficient data are

available to assess the chronic toxicity

and carcinogenic potential of methomyl.

Methomyl has been classified as a

‘‘Group E’’, i.e. the chemical is not

likely to be carcinogenic to humans via

relevant routes of exposure (HED/RfD/

Peer Review Report, October 25, 1996).

Combined chronic toxicity and

carcinogenicity study in rats. Charles

River CD rats (80/sex/group) were fed

diets containing methomyl (99+%) for 2

years at dose levels of 0, 50, 100 and 400

ppm (0, 2.5, 5.0 and 20.0 mg/kg/day,

respectively, based on the standard

conversion ratio). No significant toxicity

was observed. The NOEL is 100 ppm (5

mg/kg/day) and the LOEL is 400 ppm

(20 mg/kg/day) based on depressed

body weight gain. Methomyl was not

considered carcinogenic because there

was no evidence that the test material

increased the incidence of any

neoplastic lesion. Although the HED/

RfD Review Committee accepted the

study, the Committee determined that

the animals could have tolerated higher

doses than the highest dose level used

(MRID 00078361).

Chronic toxicity study in dogs (2-

year). Beagle dogs (4/sex/group) were

fed diets containing methomyl (90%) at

dose levels of 0, 50, 100, 400 and 1,000

ppm (0, 1.25, 2.5, 10, and 25 mg/kg/day,

respectively, based on the standard

conversion ratio) for 24 months. Two

males at the 1,000 ppm group exhibited

tremors, salivation, incoordination, and

circling movements during the 13th

week of the study. One female in the

1,000 ppm group died in the 9th week

of the study. A replaced dog exhibited

repeated convulsive seizures after 17

days of dosing and died on day 18.

There were no significant differences

among treatment and the control groups

for RBC and plasma ChE activities

which were measured at week 9 and

week 13 (high dose only) of the study.

The NOEL is 100 ppm (2.5 mg/kg/day)

and the LOEL is 400 ppm (10.0 mg/kg/

day) based on histopathological effects

in kidneys manifested as swollen/

irregular epithelial cells of the proximal

convoluted tubules as well as an

increase in the amount of pigment in the

cytoplasm of these cells (MRID

00007091).

Carcinogenicity study in mice. CD-1

mice (80/sex/group) were fed diets

containing methomyl (99+%) initially at

levels of 0, 50, 100 and 800 ppm (0, 7.5,

15 and 120 mg/kg/day, respectively,

based on the standard conversion ratio).

Due to increased mortality, the high

dose level was decreased to 400 ppm at

week 28; further, the high and mid dose

levels were reduced to 200 and 75 ppm,

respectively, at week 39 for the same

reason. These levels (50, 75 and 200

ppm) were maintained for the

remainder of the 104 week treatment

period. The highest dose level tested in

this study was considered to be

adequate for carcinogenicity testing

based on increased mortality. The

treatment did not alter the spontaneous

tumor profile in this strain of mice

under the test conditions (MRID

00078423).

Other carcinogenic issues. It should

be noted that methomyl is a metabolite

of and is structurally-related to

thiodicarb, a pesticide that was

classified as a B2 carcinogen. In

addition, acetamide, a metabolite of

methomyl, has been evaluated by the

HED/CPRC and classified as a Group C

carcinogen, possible human carcinogen.

However, after a thorough investigation,

the HED/RfD Review Committee

concluded that the ingestion of

anticipated levels of methomyl and

acetamide in the diet should not

represent a significant carcinogenic

hazard to the consuming public based

on the following:

1. The conversion rate of methomyl to

acetamide is low, approximately 2-3

percent, therefore, residue levels of

acetamide in edible meat should be low.

2. Carcinogenicity studies with

methomyl in two rodent species

indicated no increase in any type of

tumor under the test conditions.

3. The product is comprised of 98.7

percent syn-isomer and 0.092 percent

anti-isomer, syn-isomer must be

converted to anti-isomer before

acetamide is formed.

4. Acetamide induced liver tumors in

rats only when administered at very

high dosages, i.e. more than 1,000 mg/

kg/day. (HED/RfD/Peer Review Report,

October 25, 1996).

iv. Developmental toxicity. Methomyl

(99 - 100%) was administered to 25

presumed pregnant Charles River-CD

(ChR-CD) rats/group in the diet at

concentrations of 0, 50, 100 and 400

ppm (0, 4.9, 9.4 and 33.9 mg/kg/day) on

gestation days 6 through 16. The data

did not reveal any apparent

developmental toxicity. The NOEL for

maternal toxicity is 100 ppm (9.4 mg/

kg/day) and the LOEL is 400 ppm (33.9

mg/kg/day) based on decreased body

weight gain and food consumption

during gestation. The NOEL for

developmental toxicity is 400 ppm (33.9

mg/kg/day) (MRID 00008621).

Methomyl (98.7%) was administered

via stomach tube to 20 presumed

pregnant New Zealand white (DLI:NZW)

rabbits per group (19 in the high-dose

group) at dosages of 0, 2, 6 and 16 mg/

kg/day on gestation days 7 through 19.

Clinical signs indicated neurotoxic

effects in high-dose rabbits. There was

no evidence of developmental toxicity

in this study. The NOEL for

developmental toxicity is 16 mg/kg/day.

The NOEL for maternal toxicity is 6 mg/

kg/day and the LOEL is 16 mg/kg/day

based on mortalities and clinical signs

(MRID 00131257).

v. Reproductive toxicity. SpragueDawley rats in the F0 parental

generation were fed methomyl at dose

levels of 0, 75, 600 or 1,200 ppm (0,

3.75, 30, or 60 mg/kg/day, respectively,

based on the standard conversion ratio).

The F1 offspring were treated at the

same dosages. There was a dose-related

increase in clinical signs involving the

nervous system during the first few

weeks of the study and the incidence of

alopecia was increased in the 600 and

1,200 ppm group animals. The NOEL for

systemic toxicity is 75 ppm (3.75 mg/kg/

day) and the LOEL is 600 ppm (30 mg/

kg/day) based on decreased body weight

and food consumption and altered

hematology parameters. The NOEL for

reproductive toxicity is 75 ppm (3.75

mg/kg/day) and the LOEL is 600 ppm

(30 mg/kg/day) based on decreases in

both the mean number of live pups and

mean body weights of offspring (MRID

43250701).

vi. Mutagenicityy. Sufficient data are

available to satisfy data requirements for

mutagenicity testing. Technical

methomyl did not induce a genotoxic

response in any of the tests listed below.

Gene mutation. In a Chinese hamster

ovary (CHO) cells HGPRT forward gene

mutation assay, methomyl was negative

up to cytotoxic levels (≥40 mM = 6.5
44588 Federal Register / Vol. 62, No. 163 / Friday, August 22, 1997 / Rules and Regulations

mg/mL -S9; ≥150 μM = 0.24 mg/mL +S9)

(MRID 00161887).

Chromosomal aberration assay. In a

mouse micronucleus assay, methomyl

was negative in ICR mice up to an

overtly toxic dose (12 mg/kg)

administered once by oral gavage. There

was no evidence of a cytotoxic effect on

the target tissue (MRID 44047703). An

in vivo bone marrow cytogenetic assay

indicated that the test was negative in

Sprague Dawley rats up to an overtly

toxic level (20 mg/kg) administered

once by oral gavage. Target tissue

cytotoxicity was not observed (MRID

00161888).

Other genotoxic effects. Methomyl

was found to be inactive in a series of

EPA-sponsored mutagenicity studies

which included: Salmonella

typhimurium /Escherichia coli reverse

gene mutation assays, DNA damage

studies in bacteria, yeast and human

lung fibroblasts, and a Drosophila

melanogaster sex-linked recessive lethal

assay (MRID 00124901).

vii. Neurotoxicity studies. An acute

delayed neurotoxicity study with

methomyl in atropine-pretreated hens,

using the LD50 dose (28 mg/kg) as well

as higher doses, was negative (MRID

00008827).

No data are available on the acute and

subchronic neurotoxicity of methomyl

in mammals. Since methomyl is a

carbamate and neurotoxic signs have

been observed in two species (dogs and

rabbits) by two different exposure routes

(oral and dermal, respectively), acute

and subchronic neurotoxicity studies

are needed for a thorough investigation

of this parameter. A neurotoxicity

screening battery (acute and subchronic)

is required to support the re-registration

of this chemical.

B. Toxicological Endpoints

1. Acute toxicity— i. Thiodicarb. For

acute dietary exposure (1 day) the

developmental NOEL of 3 mg/kg/day

from a developmental toxicity study in

the rat is the endpoint to be used for risk

assessment for females 13+ years. This

is based on skeletal variations and

decreases in pup body weights at 10 mg/

kg/day. For the overall U.S. population,

and all other subgroups, the maternal

NOEL of 10 mg/kg/day is the endpoint

to be used for risk assessment. This is

based on the clinical signs of tremors

and inactivity at 20 mg/kg/day (LOEL).

For thiodicarb, EPA has decided that

an MOE equal to or greater than 100 is

considered to be protective. Although

there is a data gap (acute neurotoxicity

study), EPA has determined that this is

simply a confirmatory study. Other than

this study, the database is complete.

While tremors and inactivity were

observed in one developmental study,

other instances of neurotoxic behavior

have not been observed in the remaining

studies.

ii. Methomyl. For acute dietary

exposure (1 day) deaths in dams on days

1-3 after dosing at 16 mg/kg/day (LOEL)

from a developmental toxicity study in

rabbits (MRID# 00131257) was selected

as the endpoint for risk assessment. The

maternal NOEL of 6 mg/kg/day will be

used for risk assessment.

For methomyl, EPA has decided that

an MOE equal to or greater than 300 is

considered protective. For calculating

the MOE, an extra safety factor of 3 will

be used in addition to the usual 100 due

to the lack of acute and subchronic

neurotoxicity studies (data gaps) as well

as the severity of effects (death in 1-3

days) seen at the 16 mg/kg/day dose.

Unlike thiodicarb, the two neurotoxicity

studies on methomyl are critical data

gaps based on the fact that neurotoxicity

has been demonstrated in animals

studies in two species (dog, rabbit) and

by both the oral and dermal routes of

exposure. Because of the effects

observed, exposure to all population

subgroups are of concern.

2. Short - and intermediate - term

toxicity. While endpoints for short- and

intermediate- term dermal and

inhalation exposures have been

identified they are not discussed here as

they will not be used in this tolerance

assessment. Short- and intermediateterm risk analysis is conducted when

there may be primary dermal and

inhalation exposure which could result,

for example, from residential pesticide

applications. Since there are no

residential uses of thiodicarb EPA

believes that there is no exposure and

therefore no short - and intermediate -

term risk (regardless of toxicity).

3. Chronic toxicity— i. Thiodicarb.

EPA has established the RfD for

thiodicarb at 0.03 milligrams/kilogram/

day (mg/kg/day). This RfD is based on

a chronic rat toxicity study with a NOEL

of 3.3 mg/kg/day for males and 4.5 mg/

kg/day for females. The LOEL was 12

mg/kg/day for males and 15 mg/kg/day

for females, based on the increased

incidence of extramedullary

hemopoiesis in males and decreased

RBC cholinesterase in females. (MRID

43308201). An uncertainty factor (UF) of

100 was applied to account for

intraspecies variability and interspecies

extrapolation.

ii. Methomyl. EPA has established the

RfD for methomyl at 0.008 milligrams/

kilogram/day (mg/kg/day). This RfD is

based on a two-year feeding study in

dogs (MRID# 00007091) with a NOEL of

2.5 mg/kg/day. The LOEL was 10 mg/

kg/day based on histopathological

effects in kidney. An uncertainty factor

(UF) of 100 was applied to account for

both inter-species extrapolation and

intra-species variability. An extra safety

factor of 3 was applied in addition to

the 100 due to the lack of acute and

subchronic neurotoxicity studies (data

gaps).

4. Carcinogenicity— i. Thiodicarb.

The Health Effects Division

Carcinogenicity Peer Review Committee

(CPRC) classified thiodicarb as Group

B2 - probable human carcinogen

(document dated June 10, 1996).

The B2 classification was based on

statistically significant increases in

hepatocellular adenomas, carcinomas,

and combined adenoma/carcinoma in

both sexes of the CD-1 mouse at 1,000

mg/kg/day and statistically significant

increases in testicular interstitial cell

tumors in male Sprague-Dawley rats at

60 mg/kg/day.

The CPRC recommended that a nonlinear methodology (MOE) be applied

for the estimation of human risk, with

the point of departure set at the 5 mg/

kg/day dose, the lowest dose tested in

the mouse carcinogenicity study, based

on the hepatocellular combined

adenoma/carcinoma in male mice.

The CPRC felt it was inappropriate to

apply a linear low-dose extrapolation to

the animal data because the increased

incidences of tumors were statistically

significant only at the highest dose in

both species; in the case of the mice, the

highest tested dose (1,000 mg/kg/day) is

the limit dose for a carcinogenicity

study and it may have been excessive.

In addition, there was no evidence of

genotoxicity.

ii. Methomyl. The Health Effects

Division Carcinogenicity Peer Review

Committee classified methomyl as

Group E - the chemical is not likely to

be carcinogenic to humans via relevant

routes of exposure (document dated

October 25, 1996).

C. Exposures and Risks

1. From food and feed uses.

Tolerances have been established (40

CFR 180.407) for the combined residues

of thiodicarb and its metabolite

methomyl, in or on a variety of raw

agricultural commodities. Thiodicarb

has tolerances on sweet corn (2.0 ppm),

cottonseed (0.4 ppm), and soybeans (0.2

ppm). Methomyl has tolerances on

numerous crops ranging from 0.1 to 10

ppm. There are no tolerances on meat,

milk, poultry, or eggs. Risk assessments

were conducted by EPA to assess

dietary exposures and risks from

thiodicarb as follows:

i. Acute exposure and risk. Acute

dietary risk assessments are performed

for a food-use pesticide if a toxicological
Federal Register / Vol. 62, No. 163 / Friday, August 22, 1997 / Rules and Regulations 44589

study has indicated the possibility of an

effect of concern occurring as a result of

a one day or single exposure.

To estimate acute dietary exposure for

thiodicarb, the registrant conducted

Monte Carlo simulations for the overall

U.S. population, women 13 years and

older, children 1 to 6 years of age, and

infants. These analyses included

residues from field trial studies,

consumption data from the 1989

through 1992 USDA Continuing Survey

of Food Intake by Individuals (CSFII),

and information on the percentages of

the crop treated.

Food consumption data from the

USDA’s CSFII conducted from 1989

through 1992 were used to estimate

dietary exposure. The USDA provided

statistical weights that permitted the

data from the various years of the survey

to be combined.

For the acute analysis, field trial

residues were used for all crops. In

compliance with the EPA’s guidance

document, residue distributions from

field studies conducted at maximum

label conditions (e.g. maximum number

of applications, maximum application

rate, and minimum preharvest intervals)

were used for foods considered to be

single-serving commodities (e.g.

cabbage, broccoli, lettuce); mean field

trial residues were used for blended/

processed commodities (e.g. cottonseed

meal, soybean oil).

Processing factors were calculated for

cottonseed meal, cottonseed oil, and

soybean oil. These factors were used in

conjunction with the mean field trial

residues to estimate residue levels in the

processed commodities.

Residue values were adjusted for the

percent of the crop estimated to be

treated with thiodicarb. These

percentages were provided by the

Agency’s Biological and Economic

Analysis Division (BEAD). The

maximum percentage reported for a

particular crop was used in the acute

exposure analyses. Percent crop treated

information was not provided for swiss

chard, parsley, cress, and endive. The

percent crop treated for spinach was

assumed for these crops.

Acute exposure estimates to

thiodicarb were compared against the

developmental NOEL of 3 mg/kg/day

from a rat developmental study in

which decreased pup body weight was

observed. Because of the effects

observed, the population subgroup of

concern is women of child-bearing age.

For the overall U.S. population,

children 1 to 6 years of age, and infants

acute exposure estimates were

compared against the maternal NOEL of

10 mg/kg/day from a rat developmental

study based on clinical signs of tremors

and inactivity.

The MOE is a measure of how close

the high end exposure comes to the

NOEL (the highest dose at which no

effects were observed in the laboratory

test), and is calculated as the ratio of the

NOEL to the exposure (NOEL/exposure

= MOE). Generally, acute dietary MOEs

greater than 100 tend to cause no dietary

concern to the Agency when results are

compared to animal-derived data. The

MOEs for acute dietary exposure were

calculated using the estimates at the

99.9 percentile of exposure for groups of

concern. The acute exposure MOEs for

the application of thiodicarb are

presented below in Table 1.

TABLE 1. ACUTE EXPOSURE MOES

FROM THE APPLICATION OF

THIODICARB

Group of Concern Exposure NOEL MOE

U.S. Population.0 .013792 10 mg/

kg/day

218

Woman 13

years and

older.

0 .013500 3 mg/

kg/day

222

Children 1 to

6.

0 .022758 10 mg/

kg/day

439

Infants ........... 0 .010575 10 mg/

kg/day

946

The results of the acute exposure

analyses indicate that there are adequate

MOEs (equal to or greater than 100) for

the overall U.S. population, the

population subgroup of concern, women

of child bearing age, as well as for the,

infants and children from the

application of thiodicarb.

ii. Chronic exposure and risk. For

thiodicarb, a Dietary Risk Evaluation

System (DRES) chronic exposure

analysis was performed using tolerance

level residues and BEAD percent crop

treated information to estimate the

Anticipated Residue Contribution (ARC)

for the general population and 22

subgroups.

Using existing thiodicarb tolerances

result in a TMRC which represents 23%,

14%, and 36% of the RfD for the U.S.

general population, infants, and

children (1 to 6 years old). A total of

22% of the RfD is occupied by females

(13+ years, nursing) which is the highest

subgroup. If more refined estimates of

dietary exposure were made (i.e., use of

anticipated residues) lower chronic

risks would be estimated.

Even including the pending

tolerances and the higher tolerance for

cottonseed, chronic dietary risk from

food sources is not of concern.

For thiodicarb, the Cancer Peer

Review Committee recommended that a

non-linear methodology (MOE) be

applied for the estimation of human

cancer risk. The Cancer Peer Review

Committee has determined that the

NOEL of 5 mg/kg/day be used as the

point of departure for estimating human

risk. Cancer MOEs are estimated by

dividing the NOEL of 5 mg/kg/day, by

the chronic exposure. The assessment

was conducted for the Total U.S.

Population only.

Exposure = ARC = 0.007 mg/kg/day

MOE = NOEL ÷ Exposure = 5 mg/kg/

day ÷ 0.007 mg/kg/day = 714

The MOE of 714 assumes all residues

to be at tolerance level. Percent crop

treated information was utilized.

2. From drinking water. Thiodicarb

breaks down rapidly in the environment

to methomyl. Methomyl, the major

degradate of thiodicarb, is very mobile

and persists in the field for a time

sufficient (field dissipation half life = 18

days) to leach into groundwater. This

tendency is enhanced when soils are

permeable and the water table is high.

Since thiodicarb breaks down rapidly

to methomyl, EPA has estimated the

exposure and risk associated with the

highest methomyl residues detected in

ground water monitoring studies and

with the PRZM/EXAMS model numbers

for surface water.

The following assumptions have been

made to estimate exposure; water

consumption is defined as all water

obtained from the household tap that is

consumed either directly as a beverage

or used to prepare foods and beverages.

For the adult male exposure calculation,

the average adult body weight is

assumed to be 70 kg, and it is assumed

that the average adult consumes 2 liters

of water (l)/day. For children’s

exposure, the average body weight is

assumed to be 10 kg and the average

water consumption is assumed to be 1

liter per day.

The other assumption inherent in this

calculation is that water from the same

source containing the same contaminant

level is consumed throughout a 70-year

lifetime. The second of these

assumptions is extremely conservative,

since most members of the U.S.

population move at some time during

their lifetime and do not live in the

same area or drink from the same water

source for a 70-year lifetime.

Exposure is calculated using the

following formula for adults(males):

Exposure = (chemical concentration

in μg/L in ground and/or surface water)

x (10-3 mg/μg) ÷ (70 kg body weight) x

(2L water consumed/day)

For children (1 to 6 years old), the

exposure would be calculated using the

following formula:
44590 Federal Register / Vol. 62, No. 163 / Friday, August 22, 1997 / Rules and Regulations

Exposure = (chemical concentration

in μg/L in ground and/or surface water)

x (10-3 mg/μg) ÷ (10 kg body weight) x

(1L water consumed/day)

i. Acute exposure and risk. Thiodicarb

breaks down rapidly in the environment

to methomyl and methomyl is the

pesticide that was monitored in ground

water and surface water studies. The

methomyl acute dietary endpoint is

used for the acute dietary risk from

water and is based on the maternal

toxicity NOEL of 6 mg/kg/ day from the

rabbit developmental toxicity study. For

calculating the MOE, an extra safety

factor of 3 will be used in addition to

the 100 (MOE = 300) due to the lack of

acute and subchronic neurotoxicity

studies as well as the severity of effects

seen in the rabbit developmental

toxicity study.

The EPA estimate for methomyl in

ground water to be used in the acute

exposure analyses is 20 ppb and is

based on a small-scale prospective

ground water study performed by

DuPont. The EFED-supplied estimate for

methomyl in surface water is 30 ppb

which is based on a worst-case PRZM/

EXAMS run showing a concentration of

151 ppb in an agricultural farm pond

and a DuPont ecological monitoring

study showing a minimum 5-8 fold

dilution factor. The use of the 5-fold

dilution factor in estimating the

concentration in surface water thus

accounts for the high end of the possible

range.

a. Adult male acute exposure.

Methomyl exposure (highest

concentration detected in ground water)

= (20 μg/L) x (10-3 mg/μg) ÷ (70 kg body

weight) x (2L day) = 5.7 x 10-4 mg/kg/

day.

Methomyl exposure (highest

concentration modeled in surface water)

= (30 μg/L) x (10-3 mg/μg) ÷ (70 kg body

weight) x (2L day) = 8.57 x 10-4 mg/kg/

day.

The highest exposure number will be

used for acute water risk assessment for

μg/L) x (10-3 mg/μg) ÷ (70 kg body

weight) x (2L day) = 8.57 x 10-4 mg/kg/

day.

b. Children’s (1 to 6 years old) acute

exposure.

Methomyl exposure (highest

concentration detected in ground water)

= (20 μg/L) x (10-3 mg/μg) ÷ (10 kg body

weight) x (1L day) = 2.0 x 10-3mg/kg/

day.

Methomyl exposure (highest

concentration modeled in surface water)

= (30 μg/L) x (10-3 mg/μg) ÷ (10 kg body

weight) x (1L day) = 3.0 x 10-3 mg/kg/

day.

The highest exposure number will be

used for acute water risk assessment for

μg/L) x (10-3 mg/μg) ÷ (10 kg body

weight) x (1L day) = 3.0 x 10-3 mg/kg/

day.

c. Acute risk-water.

NOEL//Exposure = MOE

Adult (male) MOE = 6 mg/kg/day ÷

acute water exposure (8.57 x 10-4mg/kg/

day) = 7,001

Children’s MOE = 6 mg/kg/day ÷

acute water exposure(3 x 10-3 mg/kg/

day) =2,000

ii. Chronic exposure and risk. The

chronic estimated environmental

concentration for methomyl is 26 ppb

for surface water and 2 ppb for ground

water.

a. Adult male chronic exposure.

Methomyl exposure (average

concentration detected in ground water)

= (2 μg/L) x (10-3 mg/μg) ÷ (70 kg body

weight) x (2L day) = 5.7 x 10-5 mg/kg/

day.

Methomyl exposure (average

concentration detected in surface water)

= (26 μg/L) x (10-3 mg/μg) ÷ (70 kg body

weight) x (2L day) = 7.4 x 10-4 mg/kg/

day.

The highest exposure number will be

used for chronic water risk assessment

= 7.4 x 10-4.

b. Children’s(1 to 6 years old) chronic

exposure.

Methomyl exposure (average

concentration detected in ground water)

= (2 μg/L) x (10-3 mg/μg) ÷ (10 kg body

weight) x (1L day) = 2.0 x 10-4 mg/kg/

day.

Methomyl exposure (average

concentration modeled in surface water)

= (26 μg/L) x (10-3 mg/μg) ÷ (10 kg body

weight) x (1L day) = 2.6 x 10-3 mg/kg/

day.

The highest exposure number will be

used for acute water risk assessment for

children = 2.6 x 10-3.

c. Chronic Risk- Water. The chronic

dietary endpoint, the RfD, is 0.008 mg/

kg/day for methomyl, and is used to

calculate the chronic dietary risk. The

RfD was established based on a 2-year

dog feeding/carcinogenicity study with

a NOEL of 2.5 mg/kg/day and an

uncertainty factor of 100 to account for

both inter-species extrapolation and

intra-species variability. An additional

uncertainty factor of 3 was applied to

account for the lack of acute and

subchronic neurotoxicity studies.

The chronic dietary risk from ground

and surface water is expressed as a

percentage of the RfD through the

following formula:

chronic water exposure mg/kg/day ÷

RfD mg/kg/day x 100 = % RfD

%RfD Adult (male) = 7.4 x 10-4 ÷

0.008 mg/kg/day x 100 =9%RfD

%RfD Children(1 to 6 years) = 2.6 x

10-3 ÷ 0.008 mg/kg/day x 100 =33%RfD

3. From non-dietary exposure.

Thiodicarb is not currently registered

for any residential uses. Since there are

no residential uses of thiodicarb, EPA

does not believe that there will be any

risk associated with non-dietary

exposure.

4. Cumulative exposure to substances

with common mechanism of toxicity.

Section 408(b)(2)(D)(v) requires that,

when considering whether to establish,

modify, or revoke a tolerance, the

Agency consider ‘‘available

information’’ concerning the cumulative

effects of a particular pesticide’s

residues and ‘‘other substances that

have a common mechanism of toxicity.’’

The Agency believes that ‘‘available

information’’ in this context might

include not only toxicity, chemistry,

and exposure data, but also scientific

policies and methodologies for

understanding common mechanisms of

toxicity and conducting cumulative risk

assessments. For most pesticides,

although the Agency has some

information in its files that may turn out

to be helpful in eventually determining

whether a pesticide shares a common

mechanism of toxicity with any other

substances, EPA does not at this time

have the methodologies to resolve the

complex scientific issues concerning

common mechanism of toxicity in a

meaningful way. EPA has begun a pilot

process to study this issue further

through the examination of particular

classes of pesticides. The Agency hopes

that the results of this pilot process will

increase the Agency’s scientific

understanding of this question such that

EPA will be able to develop and apply

scientific principles for better

determining which chemicals have a

common mechanism of toxicity and

evaluating the cumulative effects of

such chemicals. The Agency anticipates,

however, that even as its understanding

of the science of common mechanisms

increases, decisions on specific classes

of chemicals will be heavily dependent

on chemical specific data, much of

which may not be presently available.

Although at present the Agency does

not know how to apply the information

in its files concerning common

mechanism issues to most risk

assessments, there are pesticides as to

which the common mechanism issues

can be resolved. These pesticides

include pesticides that are

toxicologically dissimilar to existing

chemical substances (in which case the

Agency can conclude that it is unlikely

that a pesticide shares a common

mechanism of activity with other

substances) and pesticides that produce

a common toxic metabolite (in which

case common mechanism of activity

will be assumed).
Federal Register / Vol. 62, No. 163 / Friday, August 22, 1997 / Rules and Regulations 44591

EPA does not have, at this time,

available data to determine whether

thiodicarb has a common mechanism of

toxicity with other substances or how to

include this pesticide in a cumulative

risk assessment. For the purposes of this

tolerance action, therefore, EPA has not

assumed that thiodicarb has a common

mechanism of toxicity with other

substances. However, the Agency has

determined that thiodicarb has a

metabolite which is a registered

pesticide, methomyl. Therefore, for this

tolerance determination, methomyl

residues resulting from applications of

both thiodicarb and methomyl will be

considered in a cumulative risk

assessment and compared to

appropriate toxicological endpoints for

methomyl.

D. Aggregate Risks and Determination of

Safety for U.S. Population

In examining aggregate exposure,

FQPA directs EPA to take into account

available information concerning

exposures from pesticide residues in

food and other exposures or which there

is reliable information. These other

exposures include drinking water and

non-occupational exposures, e.g., to

pesticides used in and around the home.

Risk assessments for aggregate exposure

consider both short-term and long-term

(chronic) exposure scenarios

considering the toxic effects which

would likely be seen for each exposure

duration.

Thiodicarb is a food use chemical.

There are no residential (nonoccupational) uses of thiodicarb;

therefore, the considerations for

aggregate exposure are those from food

and drinking water.

1. Acute risk. The registrant provided

an acute dietary Monte Carlo

distributional risk assessment which

combined residues of methomyl from

the application of thiodicarb and

residues of methomyl from the

application of methomyl . The

methomyl acute dietary NOEL of 6 mg/

kg/day was used to calculate the MOE.

Since methomyl, rather than

thiodicarb, per se is expected in ground

and surface water as a result of

thiodicarb applications, an acute

aggregate risk from thiodicarb residues

includes only risks from food. This

assessment is discussed in the previous

section under risk characterization for

thiodicarb.

Acute exposures to methomyl

residues from all sources (food and

water, from thiodicarb and methomyl

applications) will be aggregated and

compared to the methomyl acute dietary

NOEL. Using exposure estimates

provided by the registrant, EPA

estimated MOEs for various U.S.

subpopulations based on acute effects

and 24-hour intervals using a NOEL =

6 mg/kg BW/day. This includes residues

from methomyl in food as a result of

application of thiodicarb, from

methomyl in food as a result of

application of methomyl, and from

methomyl in water. See Table 2.

TABLE 2. EPA-ESTIMATED MARGINS OF EXPOSURE (MOES)

Population Group percentile

Food Food and Water Combined

24 hour interval 24 hour interval

mg/kg

BW/day MOE mg/kg BW/day MOE

U.S. Population

95th ................................................................................................. 0 .000349 017192 0.001206 04975

99th ................................................................................................. 0 .001099 5460 0.001956 3067

99.9th .............................................................................................. 0 .006577 0912 0.007434 807

Infants

95th ................................................................................................. 0 .000215 27907 0.003215 1866

99th ................................................................................................. 0 .000874 6865 0.003874 1549

99.9th ............................................................................................. 0 .007940 756 0.01094 548

Children 1-6 years

95th ................................................................................................. 0 .000482 12448 0.003482 1723

99th ................................................................................................. 0 .002108 2846 0.005108 1175

99.9th .............................................................................................. 0 .014396 417 0.017396 345

Overall, these estimates are likely to

be conservative estimates of the MOE.

For example, it assumes that residues,

when present, are present as a result of

application at the maximum permitted

level and observance of the minimum

PHI. No reduction as a result of

transport time from farm gate to

consumer is assumed to occur. Also, no

further reduction of residues through

washing, peeling, or cooking at the

producer or consumer level is assumed

to occur. EPA concludes that sufficient

margins of exposure exist at various

high-end percentile exposure levels of

interest (e.g., 95th, 99th, and 99.9th

percentile values) and that there are no

acute concerns associated with potential

residues of methomyl (resulting from

use of either thiodicarb or methomyl) in

foods or drinking water.

2. Chronic risk. Chronic exposures to

methomyl residues from all sources

(food and water, from thiodicarb and

methomyl applications) will be

aggregated and compared to the

methomyl reference dose. Therefore

aggregate chronic risk for thiodicarb

residues includes only risks from food

and is shown in the previous section.

Results of the chronic exposure

analysis show that no single

subpopulation exceeded 7% of the RfD.

The two most significantly exposed

subpopulations are non-nursing infants

(<1 year old) and all infants with 6.5%

and 5.2% of the RfD occupied,

respectively. For the overall U.S.

population, only 1.9% of the RfD was

occupied).

The aggregated chronic exposure from

methomyl in food as a result of

application of thiodicarb, from

methomyl in food as a result of

application of methomyl, and from

methomyl in water is shown in Table 3

below.

TABLE 3. CHRONIC AGGREGATE

EXPOSURE

Population

Subgroup

Dietary

%RfDa

Water

%RfD Totalb

U. S.

General.

1.9 9 11

Children

(1 to 6).

2.7 33 36
44592 Federal Register / Vol. 62, No. 163 / Friday, August 22, 1997 / Rules and Regulations

TABLE 3. CHRONIC AGGREGATE

EXPOSURE—Continued

Population

Subgroup

Dietary

%RfDa

Water

%RfD Totalb

Infants .... 6.5 33 40

a Dietary % RfD includes methomyl residues

from application of thiodicarb and methomyl. b Although the Novigen chronic analyses incorporated exposure to both food and water,

water concentrations were assumed in their

analyses to be 4 ppb. The Agency believes

that 26 ppb is a more appropriate estimate.

Therefore, chronic water exposure were calculated independently by the Agency using

the 26 ppb estimate. The total exposure reflected here incorporates both of these estimates and therefore slightly overestimates the

chronic risk.

3. Short- and intermediate-term risk.

Short- and intermediate-term risk

analysis is conducted when there may

be primary dermal and inhalation

exposure which could result, for

example, from residential pesticide

applications. Since there are no

residential uses of thiodicarb, EPA does

not believe that there will be any

exposure or risk associated with nonoccupational, non-water uses.

E. Aggregate Cancer Risk for U.S.

Population

Thiodicarb is a Group B2 carcinogen

(probable carcinogenic effects);

methomyl is a Group E carcinogen (no

carcinogenic effects likely). Aggregated

cancer risks are equal to the risks from

thiodicarb; there is no cancer risk added

from methomyl.

No aggregate cancer risk assessment is

required because methomyl is not a

carcinogen and methomyl, rather than

thiodicarb, per se, is expected in ground

and surface water.

F. Aggregate Risks and Determination of

Safety for Infants and Children

1. Safety factor for infants and

children— i. Thiodicarb— a. In general.

In assessing the potential for additional

sensitivity of infants and children to

residues of thiodicarb, EPA considered

data from developmental toxicity

studies in the rat, mice, and rabbit and

a two-generation reproduction study in

the rat. The developmental toxicity

studies are designed to evaluate adverse

effects on the developing organism

resulting from pesticide exposure to the

mother during prenatal development.

Reproduction studies provide

information relating to effects from

exposure to the pesticide on the

reproductive capability of mating

animals and data on systemic toxicity.

FFDCA section 408 provides that EPA

shall apply an additional tenfold margin

of safety for infants and children in the

case of threshold effects to account for

pre-and post-natal toxicity and the

completeness of the database unless

EPA determines that a different margin

of safety will be safe for infants and

children. Margins of safety are

incorporated into EPA risk assessments

either directly through use of a MOE

analysis or through using uncertainty

(safety) factors in calculating a dose

level that poses no appreciable risk to

humans. EPA believes that reliable data

support using the standard MOE and

uncertainty factor (usually 100 for

combined inter- and intra-species

variability)) and not the additional

tenfold MOE/uncertainty factor when

EPA has a complete data base under

existing guidelines and when the

severity of the effect in infants or

children or the potency or unusual toxic

properties of a compound do not raise

concerns regarding the adequacy of the

standard MOE/safety factor.

b. Developmental toxicity studies. In a

rat developmental toxicity study,

pregnant Charles River CD COBS rats

were administered thiodicarb via gavage

on gestation days 6-19 at dose levels of

0 (vehicle 0.5% methocel), 10, 20, and

30 mg thiodicarb/kg body weight/day.

In another rat developmental toxicity

study, pregnant Fisher 344 rats were

dosed via the diet on (1) gestation days

6 to 15 or (2) gestation days 0-20 at dose

levels of 0.5, 1.0, 3.0, and 100 mg

thiodicarb (>99%)/kg body weight/day.

When these two studies are considered

together, the maternal toxicity NOEL is

10 mg/kg/day, and the maternal toxicity

LOEL is 20 mg/kg/day, based on clinical

signs (tremors, inactivity). The

developmental toxicity NOEL is 3 mg/

kg/day, and the LOEL is 10 mg/kg/day,

based on decreased fetal body weights

and increased incidence of litters and

fetuses with developmental variations

which included unossification of

sternebrae #5 and/or #6 and other

sternebrae (MRIDs 00043739, 00043740,

00043741, 00053254, 00053255,

00053256).

In a developmental toxicity study,

artificially-inseminated New Zealand

white rabbits were administered

thiodicarb via gavage on gestation days

6 through 19 at dose levels of 0 (vehicle,

0.5% aqueous methylcellulose), 5, 20,

and 40 mg/kg/day. The maternal

toxicity NOEL was 20 mg/kg/day, and

the maternal toxicity LOEL was 40 mg/

kg/day, based on reduced body-weight

gain and food consumption. The

developmental toxicity NOEL was 40

mg/kg/day, the highest dose tested

(MRIDs 00159814, 40280001).

In a developmental toxicity study,

Charles River CD-1 mice were

administered thiodicarb on gestation

days 6 through 16 via gavage at dose

levels of 0 (vehicle 0.5% methocel), 50,

100, and 200 mg Thiodicarb/kg body

weight/day. The maternal toxicity NOEL

was 100 mg/kg/day, and the maternal

toxicity LOEL was 200 mg/kg/day,

based on increased mortality. The

developmental toxicity NOEL was 200

mg/kg/day, the highest dose tested

(MRIDs 00043742, 00043743, 00053257,

00053258).

c. Reproductive toxicity study. In a

two-generation reproduction study,

Crl:CD BR/VAF/Plus rats were fed doses

of 0, 5, 15, and 45 mg/kg/day of

thiodicarb. The reproductive/

developmental toxicity NOEL is 5 mg/

kg/day, and the reproductive/

developmental toxicity LOEL is 15 mg/

kg/day, based on decreased fetal body

weight and viability. The systemic

NOEL is 5 mg/kg/day and the systemic

LOEL is 15 mg/kg/day, based on

decreased body weight/gain and food

consumption in both sexes (MRIDs

42381301, 42381302, 42735101).

d. Pre- and post-natal sensitivity.

There is no evidence of additional

sensitivity to offspring following preand/or postnatal exposure to thiodicarb.

In the two-generation reproduction

study in rats, reproductive/

developmental effects in pups

(decreased body weight and viability)

were observed only at dietary levels

which were toxic in the parental

animals, as evidenced by decreased

body weight and food consumption. In

the prenatal developmental toxicity

studies in mice and rabbits, no

developmental toxicity was observed,

even at maternally toxic doses. In rats,

two prenatal developmental toxicity

studies were conducted, and based on

the combined results of these studies,

the developmental NOEL of 3 mg/kg/

day was determined. This

developmental NOEL was based upon

decreased fetal body weight and

increased incidence of delayed

ossification in the sternebrae and was

lower than the maternal NOEL of 10 mg/

kg/day, which was based upon clinical

signs of tremors and inactivity.

Although these results could indicate an

additional sensitivity of offspring to

prenatal exposure to thiodicarb, the

results are derived from two separate

studies, using two different strains of rat

(Sprague-Dawley and Wistar) which

could alter the fetal response to prenatal

exposure. Additionally, the

developmental NOEL was identified in

the second prenatal study, while all

other NOELs and LOELs were identified

in the first study. The dose level at

which the developmental NOEL was

established is, in many ways, an artifact

of dose selection, since the next higher
Federal Register / Vol. 62, No. 163 / Friday, August 22, 1997 / Rules and Regulations 44593

dose was 33 times greater than that

which demonstrated no fetal effects. If

a wide spectrum of dose levels had been

selected for testing in this strain of rat,

it is very possible that no indication of

additional fetal sensitivity would have

been observed (as they were not in the

other two studies).

e. Conclusion. Although there is a

data gap (acute neurotoxicity study),

EPA has determined that this is simply

a confirmatory study. Other than this

study, the database is complete. While

tremors and inactivity were observed in

one developmental study, other

instances of neurotoxic behavior have

not been observed in the remaining

studies. There is no evidence of

increased sensitivity to infants or

children. FQPA directs the Agency to

utilize an additional tenfold margin of

safety to protect the health of infants

and children unless the Agency

concludes based on reliable data that a

different margin will be safe for infants

and children. Based on the

considerations outlined above, the

Agency has concluded that there is

reliable data demonstrating that an

uncertainty factor of 100 is safe for

infants and children and that an

additional 10x margin of safety is not

necessary.

ii. Methomyl— a. In general. In

assessing the potential for additional

sensitivity of infants and children to

residues of methomyl, EPA considered

data from developmental toxicity

studies in the rat, mice, and rabbit and

a two-generation reproduction study in

the rat.

b. Developmental toxicity studies.

Methomyl (99 - 100%) was

administered to 25 presumed pregnant

Charles River-CD (ChR-CD) rats/group

in the diet at concentrations of 0, 50,

100 and 400 ppm (0, 4.9, 9.4 and 33.9

mg/kg/day) on gestation days 6 through

16. The data did not reveal any apparent

developmental toxicity. The NOEL for

maternal toxicity is 100 ppm (9.4 mg/

kg/day) and the LOEL is 400 ppm (33.9

mg/kg/day) based on decreased body

weight gain and food consumption

during gestation. The NOEL for

developmental toxicity is 400 ppm (33.9

mg/kg/day) (MRID 00008621).

Methomyl (98.7%) was administered

via stomach tube to 20 presumed

pregnant New Zealand white (DLI:NZW)

rabbits per group (19 in the high-dose

group) at dosages of 0, 2, 6 and 16 mg/

kg/day on gestation days 7 through 19.

Clinical signs indicated neurotoxic

effects in high-dose rabbits. There was

no evidence of developmental toxicity

in this study. The NOEL for

developmental toxicity is 16 mg/kg/day.

The NOEL for maternal toxicity is 6 mg/

kg/day and the LOEL is 16 mg/kg/day

based on mortalities and clinical signs

(MRID 00131257).

c. Reproductive toxicity study.

Sprague-Dawley rats in the F0 parental

generation were fed methomyl at dose

levels of 0, 75, 600 or 1200 ppm (0, 3.75,

30, or 60 mg/kg/day, respectively, based

on the standard conversion ratio). The

F1 offspring were treated at the same

dosages. There was a dose-related

increase in clinical signs involving the

nervous system during the first few

weeks of the study and the incidence of

alopecia was increased in the 600 and

1,200 ppm group animals. The NOEL for

systemic toxicity is 75 ppm (3.75 mg/kg/

day) and the LOEL is 600 ppm (30 mg/

kg/day) based on decreased body weight

and food consumption and altered

hematology parameters. The NOEL for

reproductive toxicity is 75 ppm (3.75

mg/kg/day) and the LOEL is 600 ppm

(30 mg/kg/day) based on decreases in

both the mean number of live pups and

mean body weights of offspring (MRID

43250701).

d. Pre- and post-natal sensitivity. In

the rat developmental toxicity study the

maternal NOEL is less than the

developmental NOEL. In the rabbit

developmental toxicity study there was

no evidence of developmental toxicity.

In the reproductive toxicity study the

systemic NOEL is equal to the

reproductive NOEL.

e. Conclusion. For calculating the

MOE, an extra safety factor of 3 will be

used in addition to the usual 100 due to

the lack of acute and subchronic

neurotoxicity studies (data gaps) as well

as the severity of effects (death in 1-3

days) seen at the 16 mg/kg/day dose.

Unlike thiodicarb, the two neurotoxicity

studies on methomyl are critical data

gaps based on the fact that neurotoxicity

has been demonstrated in animals

studies in two species (dog, rabbit) and

by both the oral and dermal routes of

exposure.

There is no evidence of increased

sensitivity to infants or children. FQPA

directs the Agency to utilize an

additional tenfold margin of safety to

protect the health of infants and

children unless the Agency concludes

based on reliable data that a different

margin will be safe for infants and

children. Based on the considerations

outlined above, the Agency has

concluded that there is reliable data

demonstrating that an uncertainty factor

of 300 is protective of infants and

children and that an additional margin

of safety is not necessary. The 300

uncertainty factor is composed of the

interspecies uncertainty factor of 10, the

intraspecies uncertainty factor of 10,

and an additional factor of 3 to

compensate for the lack of acute and

subchronic neurotoxicity studies as well

as the severity of effects (death in 1-3

days) seen at the 16 mg/kg/day dose.

2. Acute risk. For thiodicarb, to

estimate acute dietary exposure, the

registrant conducted Monte Carlo

simulations for children (1 to 6 years)

and infants. Acute dietary exposure

estimates at the 99.9 percentile of

exposure for children (1 to 6 years) and

infants resulted in MOEs of 439 and

946, respectively. The results of the

acute exposure analysis indicate that

there are adequate Margins of Exposure

(MOEs) greater than 100 for infants and

children for thiodicarb.

For methomyl, for acute aggregate risk

(from methomyl in food as a result of

application of thiodicarb, from

methomyl in food as a result of

application of methomyl, and from

methomyl in water), the dietary

exposure number (6.57 x 10-3 ) from a

Novigen Monte Carlo analysis and the

acute water exposure number (8.57 x

10-4) were combined and resulted in an

aggregate exposure of 7.43 x 10-3. When

compared against the methomyl NOEL

of 6 mg/kg/day the acute aggregate

MOEs for children (1-6 years) and

infants were 345 and 548, respectively.

The results of the acute aggregate

exposure analysis indicate that there are

adequate MOEs greater than 300 for

infants and children for methomyl.

3. Chronic risk. For methomyl, for

chronic aggregate risk, exposures (from

methomyl in food as a result of

application of thiodicarb, from

methomyl in food as a result of

application of methomyl, and from

methomyl in water) were combined and

compared to the methomyl reference

dose. The two most significantly

exposed subpopulations are nonnursing infants (<1 year old) and

children (1-6 years old) with 40% and

36% of the RfD occupied, respectively.

A thiodicarb, chronic dietary risk

assessment was conducted using

tolerance level residues and BEAD

percent crop treated information. The

chronic analysis indicates that exposure

from the existing permanent and timelimited tolerances for children(1 to 6

years old) and infants, 36% and 14%,

respectively, of the RfD would be

consumed. Chronic dietary risk

considering consumption of thiodicarb

from food sources is not of concern.

4. Short- or intermediate-term risk.

Short- and intermediate-term risk

analysis is conducted when there may

be primary dermal and inhalation

exposure which could result, for

example, from residential pesticide

applications. Since there are no

residential uses of thiodicarb, EPA does
44594 Federal Register / Vol. 62, No. 163 / Friday, August 22, 1997 / Rules and Regulations

not believe that there will be any

exposure or risk for infants or children

associated with non-occupational, nonwater uses.

III. Other Considerations

A. Metabolism In Plants and Animals

The qualitative nature of the residue

in plants is adequately understood

based on soybean, tomato, cotton, sweet

corn and peanut metabolism studies.

The residues to be regulated in plants

are thiodicarb and its metabolite

methomyl.

The qualitative nature of the residue

in animals is adequately understood

based upon acceptable ruminant and

poultry metabolism studies. The

residues to be regulated in livestock are

thiodicarb and its metabolite methomyl.

B. Analytical Enforcement Methodology

Adequate analytical methodology is

available for enforcement of tolerances

of thiodicarb. Method I in the Pesticide

Analytical Manual (PAM), Vol. II, is a

GLC/sulfur specific flame photometric

detector (FPD-S) method that has

undergone a successful EPA method

validation. The reported limit of

detection is 0.02 ppm for plant

commodities.

An enforcement analytical method for

livestock commodities is not necessary

since there are no significant animal

feed items associated with the subject

crops.

C. Magnitude of Residues

Residues of thiodicarb or its

metabolites are not expected to exceed

35 ppm in/on leafy vegetables (except

Brassicaa vegetables) and 7 ppm in/on

broccoli, cabbage, and cauliflower as a

result of this use.

D. International Residue Limits

There are no Codex, Canadian, or

Mexican tolerances for thiodicarb in/on

leafy vegetables, broccoli, cabbage or

cauliflower. Therefore, there are no

questions with respect to compatibility

of U.S. tolerances with Codex MRLs.

IV. Conclusion

Therefore, the tolerance is established

for combined residues of thiodicarb and

its metabolite methomyl in broccoli at 7

ppm, cabbage at 7 ppm, cauliflower at

7 ppm, and leafy vegetables (except

Brassica vegetables) at 35 ppm.

V. Objections and Hearing Requests

The new FFDCA section 408(g)

provides essentially the same process

for persons to ‘‘object’’ to a tolerance

regulation issued by EPA under new

section 408(e) and (l)(6) as was provided

in the old section 408 and in section

409. However, the period for filing

objections is 60 days, rather than 30

days. EPA currently has procedural

regulations which govern the

submission of objections and hearing

requests. These regulations will require

some modification to reflect the new

law. However, until those modifications

can be made, EPA will continue to use

those procedural regulations with

appropriate adjustments to reflect the

new law.

Any person may, by October 22, 1997,

file written objections to any aspect of

this regulation and may also request a

hearing on those objections. Objections

and hearing requests must be filed with

the Hearing Clerk, at the address given

above (40 CFR 178.20). A copy of the

objections and/or hearing requests filed

with the Hearing Clerk should be

submitted to the OPP docket for this

rulemaking. The objections submitted

must specify the provisions of the

regulation deemed objectionable and the

grounds for the objections (40 CFR

178.25). Each objection must be

accompanied by the fee prescribed by

40 CFR 180.33(i). If a hearing is

requested, the objections must include a

statement of the factual issues on which

a hearing is requested, the requestor’s

contentions on such issues, and a

summary of any evidence relied upon

by the requestor (40 CFR 178.27). A

request for a hearing will be granted if

the Administrator determines that the

material submitted shows the following:

There is genuine and substantial issue

of fact; there is a reasonable possibility

that available evidence identified by the

requestor would, if established, resolve

one or more of such issues in favor of

the requestor, taking into account

uncontested claims or facts to the

contrary; and resolution of the factual

issues in the manner sought by the

requestor would be adequate to justify

the action requested (40 CFR 178.32).

Information submitted in connection

with an objection or hearing request

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 information 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.

VI. Public Docket

EPA has established a record for this

rulemaking under docket control

number [OPP–300541] (including any

comments and data submitted

electronically). A public version of this

record, including printed, paper

versions of electronic comments, which

does not include any information

claimed as CBI, is available for

inspection from 8:30 a.m. to 4 p.m.,

Monday through Friday, excluding legal

holidays. The public record is located in

Room 1132 of the Public Information

and Records Integrity Branch,

Information Resources and Services

Division (7506C), Office of Pesticide

Programs, Environmental Protection

Agency, Crystal Mall #2, 1921 Jefferson

Davis Hwy., Arlington, VA.

Electronic comments may be sent

directly to EPA at:

opp-docket@epamail.epa.gov.

Electronic comments must be

submitted as an ASCII file avoiding the

use of special characters and any form

of encryption.

The official record for this

rulemaking, as well as the public

version, as described above will be kept

in paper form. Accordingly, EPA will

transfer any copies of objections and

hearing requests received electronically

into printed, paper form as they are

received and will place the paper copies

in the official rulemaking record which

will also include all comments

submitted directly in writing. The

official rulemaking record is the paper

record maintained at the Virginia

address in ‘‘ADDRESSES’’ at the

beginning of this document.

VII. Regulatory Assessment

Requirements

This final rule establishes a tolerance

under FFDCA section 408(d) in

response to a petition submitted to the

Agency. The Office of Management and

Budget (OMB) has exempted these types

of actions from review under Executive

Order 12866, entitled Regulatory

Planning and Review (58 FR 51735,

October 4, 1993). This final rule does

not contain any information collections

subject to OMB approval under the

Paperwork Reduction Act (PRA), 44

U.S.C. 3501 et seq., or impose any

enforceable duty or contain any

unfunded mandate as described under

Title II of the Unfunded Mandates

Reform Act of 1995 (UMRA) (Pub. L.

104–4). Nor does it require any prior

consultation as specified by Executive

Order 12875, entitled Enhancing the

Intergovernmental Partnership (58 FR

58093, October 28, 1993), or special

considerations as required by Executive

Order 12898, entitled Federal Actions to

Address Environmental Justice in

Minority Populations and Low-Income

Populations (59 FR 7629, February 16,

1994), or require OMB review in
Federal Register / Vol. 62, No. 163 / Friday, August 22, 1997 / Rules and Regulations 44595

accordance with Executive Order 13045,

entitled Protection of Children from

Environmental Health Risks and Safety

Risks (62 FR 19885, April 23, 1997).

In addition, since these tolerances and

exemptions that are established on the

basis of a petition under FFDCA section

408(d), such as the tolerance in this

final rule, do not require the issuance of

a proposed rule, the requirements of the

Regulatory Flexibility Act (RFA) (5

U.S.C. 601 et seq.) do not apply.

Nevertheless, the Agency has previously

assessed whether establishing

tolerances, exemptions from tolerances,

raising tolerance levels or expanding

exemptions might adversely impact

small entities and concluded, as a

generic matter, that there is no adverse

economic impact. The factual basis for

the Agency’s generic certification for

tolerance actions was published on May

4, 1981 (46 FR 24950) and was provided

to the Chief Counsel for Advocacy of the

Small Business Administration.

VIII. Submission to Congress and the

General Accounting Office

Under 5 U.S.C. 801(a)(1)(A), as added

by the Small Business Regulatory

Enforcement Fairness Act of 1996, the

Agency has submitted a report

containing this rule and other required

information to the U.S. Senate, the U.S.

House of Representatives, and the

Comptroller General of the General

Accounting Office prior to publication

of this rule in today’s Federal Register.

This is not a ‘‘major rule’’ as defined by

5 U.S.C. 804(2).

List of Subjects in 40 CFR Parts 180 and

186

Environmental protection,

Administrative practice and procedure,

Agricultural commodities, Animal

feeds, Pesticides and pests, Reporting

and recordkeeping requirements.

Dated: August 15, 1997.

Stephen L. Johnson,

Acting Director, Registration Division, Office

of Pesticide Programs.

Therefore, 40 CFR chapter I is

amended as follows:

PART 180—[AMENDED]

1. In part 180:

a. The authority citation for part 180

continues to read as follows:

Authority: 21 U.S.C. 346a and 371.

b. By revising § 180.407 to read as

follows:

§ 180.407 Thiodicarb; tolerances for

residues.

(a) General . Tolerances are

established for the combined residues of

the insecticide thiodicarb (dimethyl

N,N’-

[thiobis[[(methylimino)carbonyloxy]]

bis[ethanimidothioate]) and its

metabolite methomyl (S-methyl N-

[(methylcarbamoyl)

oxy]thioacetimidate) in or on the

following food commodities or groups.

The time-limited tolerances expire and

are revoked on the dates listed in the

following table:

Commodity Parts per million Expiration/revocation

date

Broccoli ..................................................................................................................................... 7.0 None

Cabbage ................................................................................................................................... 7.0 None

Cauliflower ................................................................................................................................ 7.0 None

Corn, sweet grain (K + CWHR) ............................................................................................... 2.0 None

Cottonseed ............................................................................................................................... 0.4 None

Cottonseed hulls ...................................................................................................................... 0.8 None

Leafy vegetables (except Brassica vegetables) ...................................................................... 35 None

Soybean hulls ........................................................................................................................... 0.8 None

Soybeans ................................................................................................................................. 0.2 None

(b) Section 18 emergency exemptions.

[Reserved]

(c) Tolerances with regional

registrations. [Reserved]

(d) Indirect or inadvertent residues.

[Reserved]

PART 186—[AMENDED]

2. In part 186:

a. The authority citation for part 186

continues to read as follows:

Authority: 21 U.S.C. 342, 348, and 701.

§ 186.5650 [Removed]

b. Section 186.5650 is removed.

[FR Doc. 97–22397 Filed 8–21–97; 8:45 am]

BILLING CODE 6560–50–F

FEDERAL COMMUNICATIONS

COMMISSION

47 CFR Part 73

[MM Docket No. 96–10; RM–8738, RM–8799,

RM–8800, RM–8801]

Radio Broadcasting Services; Ada,

Ardmore, and Comanche, OK, and

Blue Ridge, Bridgeport, Eastland,

Farmersville, Flower Mound,

Greenville, Henderson, Jacksboro,

Mineola, Mt. Enterprise, Sherman and

Tatum, TX

AGENCY: Federal Communications

Commission.

ACTION: Final rule; petition for

reconsideration.

SUMMARY: This document dismisses a

petition for reconsideration filed by

Gleiser Communications, Inc. and a

Joint Emergency Motion for Stay of

Filing Window filed by Farmersville

Radio Group, Gleiser Communications,

Inc., Hunt Broadcasting, Inc. and

Cowboy Broadcasting, L.L.C. The

original proceeding reallotted and

substituted broadcast channels or

modified authorizations at Ada,

Ardmore, and Comanche, Oklahoma,

and Bridgeport, Eastland, Farmersville,

Flower Mound, Henderson, Jacksboro,

Mineola, Mt. Enterprise, Sherman, and

Tatum, Texas. It also denied allotments

at Blue Ridge and Greenville, Texas. See

62 FR 4660, January 31, 1997. With this

action, the proceeding is terminated.

EFFECTIVE DATE: August 22, 1997.

FOR FURTHER INFORMATION CONTACT:

Robert Hayne, Mass Media Bureau,

(202) 418–2177.

SUPPLEMENTARY INFORMATION: This is a

synopsis of the Commission’s

Memorandum Opinion and Order in

MM Docket No. 96–10, adopted August

6, 1997, and released August 15, 1997.

The full text of this decision is available

for inspection and copying during

normal business hours in the FCC

Reference Center (Room 239), 1919 M

Street, NW, Washington, DC. The