Federal Register / Vol. 62, No. 122 / Wednesday, June 25, 1997 / Notices 34261

technologies that can achieve

compliance with the existing

regulations. For future regulations, EPA

must determine affordable treatment

technologies that can achieve

compliance for each of the size

categories. Within 2 years of the SDWA

Amendments of 1996, EPA must list

technologies that achieve compliance

with all existing regulations. The List of

Compliance Technologies for Small

Drinking Water Systems to meet the

present SWTR is required to be

published by August 1997.

B. Request for Stakeholder Involvement

The upcoming meeting deals

specifically with EPA’s efforts to

compile the initial list of compliance

technologies for the SWTR. EPA would

like to review the initial list of

compliance technologies with

stakeholders as well as obtain their

inputs on additional technologies that

should be considered when EPA

updates this list in a year.

The meeting will be divided into two

parts. The first part involves getting

feedback from stakeholders on the EPA

proposed list of Compliance

Technologies for the SWTR which will

be distributed in the background

materials to those registered for the

meeting. The second part involves

getting ideas and insights from

stakeholders on approaches to the

national level affordability criteria that

will be used to determine which

pathway (compliance technology or a

variance) a system will proceed along

and which technologies would be

available for the system. The issues on

affordability criteria do not apply to the

first list of technologies for the SWTR;

however, they will apply to future rules

and EPA therefore wants to begin to get

input on these issues.

The specific issues for discussion at

the meeting will be based on the abovementioned material and will include

(but may not be limited to) the

following:

1. The compliance technologies for

the filtration component of the SWTR

will include some technologies that

would fall under the ‘‘other filtration

technologies’’ as per § 141.73(d). The

pilot testing for viability would be

waived for those technologies on the

compliance technology list. These

technologies would be treated like the

filtration technologies in § 141.73(a)–(c).

Testing to ensure that the system is

capable of operating the treatment

technology may still be required for

these other filtration technologies and

the technologies directly identified in

the SWTR. What are the stakeholder’s

opinions about this approach for the

other filtration technologies?

2. Are there Point-Of-Entry units

available that could be used to meet the

requirements of the Surface Water

Treatment Rule? Is it a manageable

option?

3. The primary role of the nationallevel affordability criteria is to direct a

system either into a compliance

technology pathway or a variance

technology pathway. If the nationallevel affordability criteria are set very

high, then the variance technology

pathway will be limited or eliminated

and systems will need to install

compliance technologies. If the

national-level affordability are set very

low, the compliance technology

pathway will be limited or eliminated

and more systems will operate under

small system variances. What

components should be included in the

national-level affordability criteria?

What is the best measure of nationallevel affordability?

4. The initial list of compliance

technologies will be similar to the list of

disinfection and filtration technologies

in the SWTR. What level of detail would

stakeholders like to see on the

compliance technologies when the list

is updated in August, 1998? Is the

compliance technology list the best

mechanism to incorporate applicability

ranges?

5. Do stakeholders recommend any

specific criteria for distinguishing

treatment applications, in relation to the

3 small system categories specified

under SDWA? Would design,

operational and management capability,

chemical reactivity and/or a hazard

posed by some technologies (e.g.,

chlorine dioxide, chlorine gas) be good

parameters to consider within the

<10,000 population PWS categories?

The public is invited to provide

comments on the issues listed above

and other issues related to the List of

Compliance Technologies for Small

Drinking Water Systems and the

Affordable Criteria during the July 22–

23, 1997 meeting or in writing by

August 12, 1997.

Dated: June 19, 1997.

Cynthia Dougherty,

Director, Office of Ground Water and Drinking

Water, Environmental Protection Agency.

[FR Doc. 97–16653 Filed 6–24–97; 8:45 am]

BILLING CODE 6560–50–P

ENVIRONMENTAL PROTECTION

AGENCY

[PF–736; FRL–5719–6]

Notice of Filing of Pesticide Petitions

AGENCY: Environmental Protection

Agency (EPA).

ACTION: Notice.

SUMMARY: This notice announces the

initial filing of pesticide petitions

proposing the establishment of

regulations for residues of certain

pesticide chemicals in or on various

food commodities.

DATES: Comments, identified by the

docket control number PF–736, must be

received on or before July 25, 1997.

ADDRESSES: By mail submit written

comments to: Public Information and

Records Integrity Branch, Information

Resources and Services Division

(7506C), Office of Pesticides Programs,

Environmental Protection Agency, 401

M St., SW., Washington, DC 20460. In

person bring comments to: Rm. 1132,

CM #2, 1921 Jefferson Davis Highway,

Arlington, VA.

Comments and data may also be

submitted electronically by following

the instructions under

‘‘SUPPLEMENTARY INFORMATION.’’

No confidential business information

should be submitted through e-mail.

Information submitted as a comment

concerning this document may be

claimed confidential by marking any

part or all of that information as

‘‘Confidential Business Information’’

(CBI). CBI should not be submitted

through e-mail. Information marked as

CBI will not be disclosed except in

accordance with procedures set forth in

40 CFR part 2. A copy of the comment

that does not contain CBI must be

submitted for inclusion in the public

record. Information not marked

confidential may be disclosed publicly

by EPA without prior notice. All written

comments will be available for public

inspection in Rm. 1132 at the address

given above, from 8:30 a.m. to 4 p.m.,

Monday through Friday, excluding legal

holidays.

FOR FURTHER INFORMATION CONTACT: The

product manager listed in the table

below:
34262 Federal Register / Vol. 62, No. 122 / Wednesday, June 25, 1997 / Notices

Product Manager/Regulatory Leader Office location/telephone number Address

Elizabeth Haeberer ........ Rm. 207, CM #2, 703–308–2891, e-mail:haeberer.elizabeth@epamail.epa.gov. 1921 Jefferson Davis Hwy, Arlington, VA

Indira Gairola (Reg.

Leader).

4th floor, CS #1, 703–308–8371, e-mail: gairola.indira@epamail.epa.gov. 2800 Crystal Drive, Arlington,

VA

SUPPLEMENTARY INFORMATION: EPA has

received pesticide petitions as follows

proposing the establishment and/or

amendment of regulations for residues

of certain pesticide chemicals in or on

various food commodities under section

408 of the Federal Food, Drug, and

Comestic Act (FFDCA), 21 U.S.C. 346a.

EPA has determined that these petitions

contain data or information regarding

the elements set forth in section

408(d)(2); however, EPA has not fully

evaluated the sufficiency of the

submitted data at this time or whether

the data supports granting of the

petition. Additional data may be needed

before EPA rules on the petition.

The official record for this notice of

filing, as well as the public version, has

been established for this notice of filing

under docket control number [PF–736]

(including comments and data

submitted electronically as described

below). 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 official

record is located at the address in

‘‘ADDRESSES’’ at the beginning of this

document.

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. Comment and data will

also be accepted on disks in

Wordperfect 5.1 file format or ASCII file

format. All comments and data in

electronic form must be identified by

the docket number [PF–736] and

appropriate petition number. Electronic

comments on this notice may be filed

online at many Federal Depository

Libraries.

List of Subjects

Environmental protection,

Agricultural commodities, Food

additives, Feed additives, Pesticides and

pests, Reporting and recordkeeping

requirements.

Dated: June 9, 1997.

James Jones,

Acting Director, Registration Division, Office

of Pesticide Programs.

Summaries of Petitions

Petitioner summaries of the pesticide

petitions are printed below as required

by section 408(d)(3) of the FFDCA. The

summaries of the petitions were

prepared by the petitioners and

represent the views of the petitioners.

EPA is publishing the petition

summaries verbatim without editing

them in any way. The petition summary

announces the availability of a

description of the analytical methods

available to EPA for the detection and

measurement of the pesticide chemical

residues or an explanation of why no

such method is needed.

1. Gaylord Chemical Corporation

PP 5E4592

EPA has received a Supplement to a

Petition (PP 5E4592) from Gaylord

Chemical Corporation, P.O. Box 1209,

Slidell, LA 70459-1209, proposing,

pursuant to section 408(d)(3) the

Federal Food, Drug and Cosmetic Act,

21 U.S. C. section 346a(d), to amend 40

CFR 180.1001(d) to extend the existing

exemption from a tolerance for residues

of the inert ingredient DMSO [dimethyl

sulfoxide] by permitting its use in

pesticide formulations applied to the

edible parts of food or feed crops.

DMSO may currently be used as a

solvent or cosolvent in end-use

pesticides that are applied before crop

emergence or prior to the formation of

edible parts of food plants.

Dimethyl sulfoxide (DMSO) is widely

used as a solvent in industry, in

chemical and biochemical research, and

in medicines. DMSO readily penetrates

the skin and has proven to be an

effective carrier of various

pharmaceutical agents into the body. It

is currently used in veterinary

medicinal formulations as well as being

used medicinally in its own right.

DMSO has been shown to relieve pain

and reduce swelling when applied

dermally to acute sprains and strains. It

is approved for a variety of human

prescriptions in over 125 countries. In

the United States, DMSO is FDAapproved for treatment of

musculoskeletal injuries in horses, acute

or chronic otitis in dogs, and interstitial

cystitis in humans. In Canada, DMSO is

approved for the treatment of

scleroderma while in Germany it is

approved for the treatment of sports

injuries and in the United Kingdom for

treatment of herpes zoster.

On August 21, 1995, Gaylord

Chemical Corporation (Gaylord)

submitted to the EPA a tolerance

exemption petition (PP 5E4592) entitled

‘‘Petition for Extension of Existing

Exemption from Tolerance for the Inert

Ingredient, DMSO’’. That petition

proposed to amend 40 CFR part

180.1001(d) by allowing DMSO to be

applied to the edible parts of food and

feed crops when used in end-use

pesticide formulations as a solvent or a

cosolvent at up to 10 percent of finished

sprays or tank mixes. Gaylord now

proposes to amend their petition to

clarify that DMSO is intended for

applications at not more than 5 lbs.

DMSO per acre when used as a solvent

or cosolvent in end-use pesticide

formulations applied to the edible parts

of food and feed crops.

Pursuant to the section 408(d)(2)(A)(i)

of the FFDCA, as amended, Gaylord

Chemical Corporation has submitted the

following summary of information, data

and arguments in support of their

tolerance exemption petition. This

summary was prepared on behalf of

Gaylord Chemical Corporation and EPA

has not fully evaluated the merits of the

petition. The summary may have been

edited by EPA if the terminology used

was unclear, the summary contained

extraneous material, or the summary

was not clear that it reflected the

conclusion of the petitioner and not

necessarily EPA.

Based on petition PP 5E4592, as

amended, by the supplemental

information presented herein, Gaylord

Chemical Corporation concludes that

the expanded use of DMSO in pesticide

end-use formulations applied to the

edible parts of food and feed crops will

not result in DMSO dietary exposures of

toxicological consequence for the

following reasons: (1) DMSO is widely

distributed and naturally-occurring in

plants and the environment; (2) DMSO

is extensively metabolized by plants

following either root or foliar uptake; (3)

When ingested or dermally applied,
Federal Register / Vol. 62, No. 122 / Wednesday, June 25, 1997 / Notices 34263

DMSO is practically non acutely toxic,

nor is it genotoxic or carcinogenic; (4)

DMSO is rapidly metabolized and

excreted by animals and humans

without any evidence of

bioaccumulation; (5) DMSO is not

anticipated to cause any cumulative

effects; and (6) There is no evidence that

DMSO is an endocrine disruptor.

A. Proposed Use Practices of DMSO

DMSO is a pesticidally inert

ingredient that currently is exempted

[40 CFR (180.1001(d)] from the

requirement of a tolerance for residues

when used as a solvent or cosolvent in

pesticide formulations applied before

crop emergence from the soil or prior to

formation of edible parts of food plants.

There are no other limits for DMSO

expressed in 40 CFR (180.1001(d). The

proposed amended use would allow

DMSO applications at not more than 5

lbs. DMSO per acre when used as a

solvent or cosolvent in end-use

pesticide formulations applied to the

edible parts of food and feed crops.

B. Natural Occurrence of DMSO

Researchers have estimated that

approximately 20 - 60 billion pounds of

DMSO are created in the atmosphere

each year from naturally-occurring,

atmospheric dimethyl sulfide (DMS).

DMSO is also found in natural waters,

where it is believed to be produced by

photochemical oxidation of dimethyl

sulfide (DMS) generated by algae and

phytoplankton. There is also evidence

that DMSO is found naturally in soils

and is metabolized by a variety of

microorganisms, resulting in

volatilization of sulphur from soil.

Naturally-occurring DMSO has been

identified in alfalfa, asparagus, barley,

beans, beets, cabbage, corn, cucumbers,

oats, onions, Swiss chard, tomatoes,

apples, raspberries, spearmint, beer,

milk, coffee and tea. DMSO

concentrations in fresh fruit, vegetables

and grains ranged from undetectable

(<0.05 parts per million (ppm) to 1.8

ppm. In processed products such as

sauerkraut or tomato paste,

concentrations of DMSO ranged from

<0.05 to 3.7 ppm. DMSO was also found

in milk (0.13 ppm), lager beer (1.4 ppm),

coffee (2.6 ppm) and black tea (16.0

ppm). In forage crops such as alfalfa and

corn silage, DMSO levels were 0.17 and

0.31 ppm, respectively.

C. Product Identity/Chemistry

1. Identity of inert compound and

corresponding residues. Dimethyl

sulfoxide (CAS number 67–68–5) is

commonly known and abbreviated as

DMSO. Other names for DMSO are

sulfinylbismethane and methyl

sulfoxide. The molecular weight of

DMSO is 78.13, the empirical formula is

C2H6SO, and the structural formula is

(CH3)2SO. DMSO is a very hygroscopic

liquid with practically no odor or color.

Residues of DMSO include DMSO2

(dimethyl sulfone) and DMS (dimethyl

sulfide).

2. Plant metabolism. The metabolism

of DMSO in plants is well understood.

Extensive studies have shown that: (1)

DMSO is absorbed by plant roots and

foliage; (2) translocation of DMSO is

primarily upward and associated with

the transpirational stream; (3)

metabolism of DMSO is primarily

occurs in the foliage; (4) DMSO is

metabolized to DMSO2 by oxidation, to

volatile DMS by reduction and to

components that are incorporated into

sulfur-containing amino acids and

proteins; (5) DMSO does not accumulate

in plant tissues; and (6) the amount of

residue is dependent on the time since

application.

3. Analytical methods. Validated

analytical methods for residues of

DMSO in or on plant and animal tissues

are available. DMSO is extracted from

the samples, analyzed by gas

chromatography using a flame

photometric detector operating in the

sulfur mode and quantified by

comparison to external standards.

4. Magnitude of the residues. In 1

study, 15 food or feed crops were

treated with DMS35O at a rate of 5 lbs

per acre 24 hours before harvest. The

maximum total radioactive residue

(TRR) found in forage crops was 39.16

ppm. Among the food crops, grain from

fall-planted barley had maximum total

S35 residues (5.38 ppm), while red

raspberries had residues of 1.81 ppm.

All of the other treated crops had

residues less than 1 ppm with those in

or on sweet corn, cabbage, apples,

onions and dried beans at less than 0.01

ppm.

A series of studies were also

conducted to determine the types of

residues and the level of S35 in milk

and tissues of lactating goats and in eggs

and tissues of chickens fed 20, 60 or 200

ppm DMS35O in the diet for 28 days.

Summary results are: (1) the maximum

amounts of DMS35O in milk, eggs, and

goat and chicken tissues from the 20

ppm DMS35O feeding level were 0.06,

0.28, 0.20 and 0.44 ppm, respectively,

and TRR was 0.64, 3.00, 3.86 and 2.13

ppm, respectively ; (2) most of the

DMS35O activity fed to the test animals

was eliminated or metabolized to

DMS35O2 and higher molecular weight

S35-bearing compounds; (3) total S35

and DMS35O activities in milk and eggs

remained fairly constant within each

feeding level for the 28-day feeding

period (i.e., no accumulation of S35

activity with time); (4) there was no

accumulation of total S35 activity in

chicken and goat tissues at any feeding

level; and (5) the largest amounts of

total S35 activity were found in goat

liver and kidney and in chicken liver

and muscle.

D. Toxicological Profile

1. Acute toxicity. DMSO has low acute

toxicity and is practically non-toxic

(LD50 > 5 g/kg) by ingestion or dermal

application. Rat oral LD50s are reported

from 14.5 to 28.3 g/kg, whereas LD50s

for mice have been reported from 16.5

to 24.6 g/kg. The acute dermal LD50 is

40 g/kg for the rat and 50 g/kg for the

mouse, while dermal LD50s > 11 g/kg are

reported for both dogs (beagles) and

primates (rhesus monkeys). The acute

rat inhalation LC50 > 1.6 mg/l, the only

dose level tested, and which is also the

no-observed-effect-level (NOEL).

Although DMSO can cause skin and eye

irritation, it is not a skin sensitizer.

2. Genotoxicity. DMSO is not

mutagenic to Salmonella, Drosophila,

and fish cell cultures. Because DMSO is

not considered to be mutagenic, it is

widely used as a solvent in

mutagenicity testing. Although DMSO is

bacteriostatic or bactericidal at

concentrations of 5-50 percent, there is

no evidence that DMSO causes

chromosomal aberrations at levels that

are not directly toxic to cells. In vivo

cytogenetic studies with primates

receiving orally or dermally

administered DMSO showed no

abnormalities in bone marrow smears.

There are no documented adverse

genetic effects reported as a result of

medicinal DMSO uses (including quasimedicinal uses for treatment of arthritis

or sprains and strains). Additionally, no

adverse genetic effects have been

reported from occupational exposure to

DMSO in over 40 years of industrial use.

3. Reproductive and developmental

toxicity. A mouse teratology NOEL of 12

g/kg/day has been established based on

research with a 50 percent DMSO

solution administered orally. Additional

teratogenicity studies of orally

administered DMSO to pregnant mice,

rats, rabbits and guinea pigs have

demonstrated that DMSO is not a

teratogen in mammals except at high

levels that cause overt maternal toxicity

and are coincident with the maximum

tolerated dose. The data suggest that

DMSO is not teratogenic at low levels

regardless of the route of administration.

Finally, the teratogenic potential of

DMSO is dependent on the route of

administration, the dose level and

gestation stage at exposure.
34264 Federal Register / Vol. 62, No. 122 / Wednesday, June 25, 1997 / Notices

4. Subchronic toxicity. A subchronic

rat inhalation study established a NOEL

at 200 mg/m3 (0.2 mg/l), the only

concentration tested. Extensive

monitoring of human patients have

shown that DMSO does not affect

human renal function. DMSO is a

diuretic but no sign of kidney damage

has been found in humans or laboratory

animals after repeated DMSO treatment.

5. Chronic toxicity. DMSO is not

listed as a carcinogen by IARC, NTP,

OSHA or ACGIH, based on reviews of

numerous studies. In fact, a study

supported by the US Public Health

Services concluded that DMSO was not

a carcinogen and is a safe carrying agent

analogous to mineral oil. An 18–month

study with rhesus monkeys established

an oral NOEL of 3 g/kg/day. No tumors

were observed and bone marrow smears

from the monkeys that received oral or

topical doses of DMSO at up to 9 g/kg/

day for 18 months showed no DMSO

effects. A 78–week rat study revealed no

increases in mortality or tumors and

established an oral NOEL of 3.3 g/kg/

day based on hematology and ocular

effects. If one considers the rhesus

monkey to be the most appropriate

model for extrapolation to humans, the

oral monkey NOEL of 3 g/kg/day is

comparable to an average human (70 kg)

consuming approximately 210 g DMSO

per day. Continuing research has

demonstrated that the ocular effects

reported from DMSO treatment of dogs,

rabbits, guinea pigs and swine are

species-specific and not reproducible in

primates, including humans. In fact, 84

humans that have received daily topical

treatment of 2.6 g DMSO/kg/day for up

to 3 months showed no DMSO-related

effects beyond occasional skin irritation

and garlicky breath and body odor.

6. Human and animal metabolism.

DMSO is metabolized in humans by

oxidation to DMSO2 or by reduction to

DMS. DMSO and DMSO2 are excreted

in the urine and feces. DMS is

eliminated through the breath and skin

with a characteristic garlicky or oysterlike odor. Human excretion of orally

administered DMSO is complete within

120 hours, with up to 68 percent as

unchanged DMSO and 21-23 percent as

DMSO2 excreted in the urine. The rate

of renal clearance has been shown to be

similar for chronic and singly

administered doses regardless of dose

concentration. No residual

accumulation of DMSO has been

reported in humans or lower animals

who have received DMSO treatment for

protracted periods of time, regardless of

route of dose administration.

7. Metabolite toxicity. The metabolites

of DMSO are DMSO2, which is

naturally-occurring at low levels in

human urine, and DMS, which is

naturally-occurring in plants, the

atmosphere, and lakes and oceans. Both

of these metabolites are readily excreted

from the body. Based on their

widespread natural occurrence and

ready degradation and/or excretion, the

production of these metabolites from the

proposed use of DMSO on food

producing plants is not expected to pose

any toxicological concern.

E. Aggregate Exposure

1. Dietary exposure. While potential

dietary exposure is usually determined

by multiplying the residue tolerance

level for each exposed food or feed crop

by its dietary consumption data then

summing the residue contributions from

all dietary sources, this method is not

possible for DMSO for the following

reasons: (1) because DMSO is naturallyoccurring in many plants as well as in

natural waters, the daily intake of

endogenous DMSO is unknown; (2)

residue data are only available for some

of the raw agricultural commodities

(RAC) that may potentially be exposed

to DMSO from its proposed use in

pesticides; and (3) it is unknown at this

time which RACs will be exposed to

DMSO used in pesticides applied to

edible crop parts.

However, one can broadly estimate

dietary exposure based on certain

assumptions and/or generalizations, the

available residue data to estimate

conservative residue levels in broad

crop groupings, and dietary

consumption information for categories

of food commodities. For example,

information on per capita consumption

data provided by food and nutrition

specialists allows the following estimate

of daily food consumption: meat - 0.5

lbs, dairy - 1.0 lbs, fruit and vegetables

- 2.0 lbs and grains - 2.0 lbs, for a daily

food consumption of 5.5 lbs or 2.5 kg

food per day.

2. Food. When DMSO is applied at up

to 5.0 lbs/acre to the edible parts of food

and feed crops, dietary exposure to

DMSO can be estimated from naturallyoccurring DMSO levels in various food

and feedstuffs in combination with

those from crops harvested 24 hours

after DMSO application. Maximum

theoretical DMSO residues were 0.5 to

4 ppm in or on fruits and vegetables, up

to about 10 ppm in or on small grains,

and up to about 40 ppm in or on forage

grasses and legumes.

Theoretical residues of DMSO in the

human diet from meat and dairy

products were determined from

theoretical animal diets, the available

crop residue data converted to dry

weight basis and residue data from

animal feeding studies. Based on these

estimates of DMSO in bovine and

poultry diets, bovine meat (liver) and

milk would contribute 19.2 ppm and 8.0

ppm DMSO to the human diet,

respectively, while poultry meat (liver)

and eggs would contribute 2.1 ppm and

3.0 ppm DMSO to the diet.

Using the available residue data for

DMSO in the raw agricultural

commodities (RACs) and animal

products in concert with dietary

consumption information, total daily

dietary intake of DMSO in human diet

would be 0.0207 g (20.7 mg) DMSO.

DMSO levels (ppm) in the human diet

from endogenous sources and the

proposed uses of DMSO in pesticide

formulations are estimated to be 8.66

ppm. For dietary risk calculations, a

more conservative value of 10.0 ppm

will be used for estimated DMSO levels

in human diet.

3. Drinking water. Based on the

natural occurrence of DMSO in the

environment, its chemical and

biological characteristics and little-to-no

mobility in soil, the expanded

agronomic usage of DMSO is not

expected to significantly increase

drinking water exposures to DMSO.

DMSO is found in many natural waters

but concentrations are dependent on

DMSO producing algae and other

natural variables. It is unknown if or at

what levels DMSO would be found in

municipal or private water systems. Any

DMSO that may be oversprayed to the

soil from applications to crops would be

rapidly metabolized by a wide variety of

microorganisms, thereby diminishing

ground or surface water exposure to

DMSO. Additionally, environmental

studies have shown little-to-no mobility

of DMSO in the soil. Finally, DMSO is

already cleared as a pesticidal inert for

use in products applied to crops.

Therefore, the proposal to expand the

application timing of DMSO from early

in the cropping season to include the

entire cropping season would not be

expected to significantly increase

exposure of drinking water sources to

DMSO.

4. Non-dietary exposure. The only

anticipated human exposure to DMSO

from non-dietary sources would be

through occupational exposure,

medicinal or quasi-medicinal uses of

DMSO. DMSO applied to plants is

rapidly absorbed and metabolized.

When oversprayed to soils during

agronomic use, DMSO is metabolized by

a wide variety of soil microorganisms.

DMSO is legally and readily available in

health stores in many states and is

reportedly used as a unregistered topical

treatment for arthritis, muscle strains

and sprains and bursitis. However,

while these uses are not FDA-approved,
Federal Register / Vol. 62, No. 122 / Wednesday, June 25, 1997 / Notices 34265

they have been practiced for 30 to 40

years with no documented ill effects

beyond skin irritation to humans.

Dermal exposure to very low levels of

naturally-occurring DMSO may also

occur from swimming in lakes or in the

ocean.

F. Cumulative Effects

There is no reliable information to

indicate that DMSO has a common

mechanism of toxicity with any other

chemical compound. Therefore, for

cumulative exposure considerations,

Gaylord believes it is appropriate to

consider only the potential risks of

DMSO.

Metabolism studies in humans and

animals have shown that DMSO is not

bioaccumulative. Since DMSO is

naturally-occurring in many if not most

fruits, vegetables and grains, is readily

metabolized and eliminated, and has

low toxicity, there would not be any

anticipated increased human risk or

adverse effects from DMSO applied to

edible parts of plants. Plant-eating

animals, including humans, ingest

endogenous DMSO on a daily basis

throughout their life as part of the

normal diet. Ingestion of low-level

DMSO residues resulting from

agronomic use of DMSO will not

increase the body burden of this

efficiently metabolized and excreted

compound.

G. Endocrine Effects

In light of the ubiquitous natural

occurrence of this compound and the

absence of any reported endocrine

effects from any of the toxicity studies

(even at very high dose levels), DMSO

is not considered to be an endocrine

disruptor. DMSO is found naturally in

the environment, in natural waters and

in most foods and feeds. Studies have

shown that DMSO applied to plants is

metabolized and incorporated into

amino acids and other sulfur-containing

plant components. Animal and human

metabolism studies have shown that

DMSO is predominantly eliminated ‘‘as

is’’ or metabolized to DMSO2 and DMS

prior to elimination. Several studies in

which different species (i.e. rat, mouse,

rabbit, hamster) were administered

DMSO at high levels (up to lethal levels)

have shown no effect on the time-tomating or on mating and fertility

indices. Radiolabeled DMS35O fed to

chickens (laying hens) for 28 days had

no effect on the ability of the hens to

produce eggs. This wealth of data

suggests that there are no effects on the

estrous cycle, on mating behavior, or on

male or female fertility. Chronic and

subchronic studies in rhesus monkeys,

mice, rats and dogs have not

demonstrated any evidence of toxicity

to the male or female reproductive

tracts.

H. Safety Determination

1. US population. Based on the

human NOEL of 2.6 g/kg/day and very

conservative assumptions about DMSO

residue levels in food/feed from natural

occurrence and from the proposed

expanded agronomic usage of DMSO, it

would be impossible for humans to

ingest toxicologically consequential

levels of DMSO. DMSO is naturally

present in most edible plants and

animal products (i.e. milk, eggs, etc.).

The proposed use of DMSO on edible

parts of food crops would not add

appreciably to naturally-occurring

DMSO levels except for forage crops.

Even when residues in or on forage

crops and maximum anticipated

residues from animal tissues/products

are considered, total theoretical

maximum levels of DMSO in the diet

are still considerably below levels that

would be of toxicological concern.

There is ample information to

determine a reference dose (RfD) of 0.03

g DMSO/kg body weight/day based on

data from chronic oral studies with

rhesus monkeys. NOELs established by

chronic oral studies vary from 3.0 g/kg/

day for a monkey oral study to 12 g/kg/

day for a mouse teratology study. Since

dogs are the most sensitive specie tested

using the oral route of exposure, based

on lenticular effects, it would seem

appropriate to use a dog study to

establish the RfD for conducting a

dietary exposure assessment. However,

since rhesus monkeys are

physiologically more closely related to

humans than dogs, and the lenticular

effect observed in dogs has never been

documented in primates or humans in

over 30 years of testing, the primate oral

NOEL of 3 g/kg/day would be more

relevant for use in human dietary risk

assessments. Since the NOEL was

established in a non-human it is

appropriate to use an uncertainty factor

(UF) of 100X (using current EPA criteria

of 10X for intra-species variability and

10X for inter-species variability, 10 x 10

= 100). The data from the

multigeneration studies indicate that

there is no increased risk to neonates or

young when DMSO is administered

orally; therefore, an extra safety factor

for the protection of infants and

children is not warranted. This would

result in a UF of 100X and a RfD of 0.03

g/kg/day or 30 mg/kg/day DMSO. For an

average adult (70 kg) this is equivalent

to 2.1 g DMSO/day, which is lower than

therapeutic levels (i.e., 2.6 g/kg/day)

that have shown no adverse effects in

humans.

Since the RfD of 0.26 g/kg/day

calculated from human data is based on

a 3–month exposure period, the more

conservative RfD of 0.03 g/kg/day

calculated from monkey data, based on

a 18–month exposure period, will be

used in conducting the DMSO lifetime

risk assessment. Using the compounded

and extremely conservative exposure

assumptions described above and the

very conservative RfD of 0.03 g DMSO/

kg/day, the aggregate human exposure

to DMSO from its proposed agronomic

use will utilize only 0.99 percent

[(0.0207 g DMSO/day in diet) ( (0.03 g/

kg/day x 70 kg body wt) = 0.0207g

DMSO/day anticipated ( 2.1 g/day

DMSO allowed = 0.00985] of the RfD for

the US population (based on estimated

average consumption of 2.5 kg food/day

for an average 70 kg adult). EPA

generally has little concern for

exposures below 100 percent of the RfD

because the RfD represents the level at

or below which daily aggregate dietary

exposure over a lifetime will not pose

appreciable health risks to humans.

Thus, based on the natural occurrence

of DMSO in the human diet, DMSO’s

low toxicity, the ability of humans to

readily metabolize DMSO, and very low

aggregate dietary exposure, Gaylord

concludes with reasonable certainty that

no harm will result from aggregate

human exposure to residues from the

proposed use of DMSO in pesticide

products applied to the edible parts of

food and feed crops.

2. Infants and children. The proposed

use of DMSO in pesticide products

applied to the edible parts of plants will

pose no additional risk of adverse

effects to infants or children. Human

infants and children are exposed to

endogenous levels of DMSO and readily

metabolize and excrete this compound.

Even so, when assessing the potential

for additional sensitivity of infants and

children to DMSO and its residues, it is

appropriate to consider the results of the

developmental and reproductive

studies, chronic studies and human

health studies. The available data

provide a clear picture of possible toxic

effects and indicate that there is no

increased risk to neonates or young

when DMSO is ingested. Therefore,

Gaylord concludes that an additional

safety factor for the protection of infants

and children is not needed and that the

RfD of 0.03 g/kg/day is appropriate for

assessing DMSO risks to infants and

children.

Using the conservative exposure

assumptions previously described, the

percent RfD utilized by the aggregate

human exposure to residues of DMSO

from natural occurrence and from the

proposed use would be 1.2 percent
34266 Federal Register / Vol. 62, No. 122 / Wednesday, June 25, 1997 / Notices

[(0.0207 g DMSO/day in diet) x (0.25

percent of adult intake) ( (0.03 g/kg/day

x 14 kg body wt) = 0.0052 g DMSO/day

anticipated ( 0.42 g/day DMSO allowed

= 0.0123] for children 1 to 6 years old,

based on estimated average

consumption of 0.625 kg food/day (1/4

of adult consumption) and average body

weight of 14 kg. Therefore, based on this

conservative exposure assessment,

Gaylord concludes with reasonable

certainty that no harm will result to

infants and children from aggregate

human exposure to residues from the

proposed use of DMSO in pesticide

products applied to the edible parts of

food and feed crops.

I. Existing Tolerances

DMSO is a pesticidally inert

ingredient that currently is exempted

[40 CFR (180.1001(d)] from the

requirement of a tolerance for residues

when used as a solvent or cosolvent in

pesticide formulations applied before

the crop emergence from the soil or

prior to formation of edible parts of food

plants. There are no other limits for

DMSO expressed in 40 CFR

(180.1001(d).

J. International Tolerances

There are no Codex maximum residue

levels established for residues of DMSO

on food or feed crops.

2. Gustafson Incorporation

PP 5F4584

EPA has received a pesticide petition

(PP 5F4584) pursuant to section 408(d)

of the Federal Food, Drug and Cosmetic

Act, as amended, 21 U.S.C. 346a(d), by

the Food Quality Protection Act of 1996

(Pub. L. 104-170, 110 Stat. 1489) from

Gustafson, Inc., 1400 Preston Road,

Suite 400, Plano, Texas 75093

requesting that the time limited

tolerances for wheat, barley and sugar

beet RACs be made permanent for

residues of the insecticide,

imidacloprid: 1-[(6-chloro-3-

pyridinyl)methyl]-N-nitro-2-

imidazolidinimine and its metabolites

containing the 6-chloro-pyridinyl

moiety. In September 1995, the EPA

revised Table II of the Pesticide

Assessment Guidelines, Subdivision O,

Residue Chemistry. At that time, forage

was removed as a raw agricultural

commodity of barley. It is proposed that

tolerances of 0.20 ppm for wheat, hay,

and 0.20 ppm for barley, hay, be added.

It is proposed that the tolerance for

barley, straw, be increased from 0.20

ppm to 0.30 ppm. It is proposed that the

tolerance for beets, sugar (tops) be

increased from 0.20 ppm to 0.30 ppm.

The original time-limited tolerances

were published in the December 13,

1995 and in the August 30, 1995

Federal Registers. Imidacloprid is a

broad-spectrum insecticide with

excellent systemic and contact toxicity

characteristics which is used primarily

for sucking insects. The nature of the

imidacloprid residue in plants and

livestock is adequately understood. The

analytical method for determining

residues is a common moiety method

for imidacloprid and its metabolites

containing the 6-chloro-pyridinyl

moiety using oxidation, derivatization,

and analysis by capillary gas

chromatography with a mass-selective

detector. Pursuant to section

408(d)(2)(A)(i) of the FFDCA, as

amended, Gustafson has submitted the

following summary of information, data

and arguments in support of its

pesticide petition. The summary was

proposed by Gustafson, and EPA has not

yet fully evaluated the merits of the

petition. The conclusions and

arguments presented are those of the

petitioner and not of the EPA although

the EPA has edited the summary for

clarification as necessary.

A. Plant Metabolism and Analytical

Method

The metabolism of imidacloprid in

plants is adequately understood for the

purposes of these tolerances. The

residues of concern are combined

residues of imidacloprid and its

metabolites containing the 6-chloropyridinyl moiety, all calculated as

imidacloprid. The analytical method is

a common moiety method for

imidacloprid and its metabolites

containing the 6-chloro-pyridinyl

moiety using a permanganate oxidation,

silyl derivatization, and capillary GCMS selective ion monitoring. This

method has successfully passed a

petition method validation in EPA labs.

There is a confirmatory method

specifically for imidacloprid and several

metabolites utilizing GC/MS and HPLCUV which has been validated by the

EPA as well. Imidacloprid and its

metabolites are stable for at least 24

months in the commodities when

frozen.

B. Magnitude of the Residue

1. Wheat. When the conditional

registrations and the time-limited

tolerances were issued for wheat grain,

wheat forage and wheat straw, the EPA

requested additional residue field trials

and residue testing to support a

tolerance for wheat hay. Wheat seed was

treated with imidacloprid, formulated as

Gaucho 480 FS at a rate of 2.0 oz. a.i./

cwt seed. Field trials were conducted at

seven locations: Colorado, Nebraska

(two locations), North Dakota,

Oklahoma, Texas and Wyoming. The

wheat seed was planted and the RACs

were harvested at the appropriate

growth stages. Maximum residues in

wheat grain, wheat forage and wheat

straw were less than the time-limited

tolerances. The maximum residue level

in wheat hay was 0.187 ppm. A

tolerance of 0.20 ppm for wheat hay is

proposed.

2. Barley. When the conditional

registrations and the time-limited

tolerances were issued for barley grain,

barley forage and barley straw, the EPA

requested additional residue field trials

and residue testing to support a

tolerance for barley hay. Barley seed

was treated with imidacloprid,

formulated as Gaucho 480 FS at a rate

of 2.0 oz. a.i./cwt seed. Field trials were

conducted at five locations: Colorado,

Nebraska, North Dakota, Pennsylvania

and Wyoming. The barley seed was

planted and the RACs were harvested at

the appropriate growth stages. The

maximum residue in barley grain was

less than the time-limited tolerance. The

maximum residue level in barley straw

was 0.221 ppm, which was above the

time- limited tolerance of 0.20 ppm. A

revised tolerance of 0.30 ppm for barley

straw is proposed. The maximum

residue level in barley hay was 0.181

ppm. A tolerance of 0.20 ppm for barley

hay is proposed.

3. Sugar Beets. When the conditional

registrations and the time-limited

tolerances were issued for beets, sugar

(tops); beets, sugar (roots); and beets,

sugar, molasses; the EPA requested

additional residue field trials. Sugar

beet seed was treated with imidacloprid,

formulated as Gaucho 75 ST at a rate of

90 g ai/kg raw seed. Field trials were

conducted at four locations: California,

Colorado, Idaho and Nebraska. The

sugar beet seed was planted and the

RACs were harvested at the appropriate

growth stages. The maximum residue in

the sugar beet roots was less than the

time-limited tolerances. The maximum

residue level in the sugar beet tops was

0.255 ppm, which was above the timelimited tolerance of 0.10 ppm. A revised

tolerance of 0.30 ppm for sugar beet tops

is proposed.

C. Toxicological Profile of Imidacloprid

1. Acute toxicity. The acute oral LD50

values for imidacloprid technical ranged

from 424 - 475 mg/kg bwt in the rat. The

acute dermal LD50 was greater than

5,000 mg/kg in rats. The 4–hour

inhalation LC50 was less than 69 mg/m3

air (aerosol). Imidacloprid was not

irritating to rabbit skin or eyes.

Imidacloprid did not cause skin

sensitization in guinea pigs.
Federal Register / Vol. 62, No. 122 / Wednesday, June 25, 1997 / Notices 34267

2. Genotoxicity. Extensive

mutagenicity studies conducted to

investigate point and gene mutations,

DNA damage and chromosomal

aberration, both using in vitro and in

vivo test systems show imidacloprid to

be non-genotoxic.

3. Reproductive and developmental

toxicity. A 2–generation rat

reproduction study gave a no-observedeffect level (NOEL) of 100 ppm (8 mg/

kg/bwt). Rat and rabbit developmental

toxicity studies were negative at doses

up to 30 mg/kg/bwt and 24 mg/kg/bwt,

respectively.

4. Subchronic toxicity. 90–day feeding

studies were conducted in rats and

dogs. The NOELs for these tests were 14

mg/kg/bwt/day (150 ppm) and 5 mg/kg/

bwt/day (200 ppm), for the rat and dog

studies, respectively.

5. Chronic toxicity/oncogenicity. A 2–

year rat feeding/ carcinogenicity study

was negative for carcinogenic effects

under the conditions of the study and

had a NOEL of 100 ppm (5.7 mg/kg/bwt

in males and 7.6 mg/kg/bwt in females

for noncarcinogenic effects that

included decreased body weight gain in

females at 300 ppm and increased

thyroid lesions in males at 300 ppm and

females at 900 ppm. A 1–year dog

feeding study indicated a NOEL of 1,250

ppm (41 mg/kg/bwt). A 2–year mouse

carcinogenicity study was negative for

carcinogenic effects under conditions of

the study and had a NOEL of 1,000 ppm

(208 mg/kg/day).

Imidacloprid has been classified

under ‘‘Group E’’ (no evidence of

carcinogenicity) by EPA’s OPP/HED’s

Reference Dose (RfD) Committee. There

is no cancer risk associated with

exposure to this chemical. The reference

dose (RfD) based on the 2–year rat

feeding/carcinogenic study with a NOEL

of 5.7 mg/kg/bwt and hundredfold

uncertainty factor, is calculated to be

0.057 mg/kg/bwt. The theoretical

maximum residue contribution (TMRC)

from published uses is 0.008358 mg/kg/

bwt/day utilizing 14.7 percent of the

RfD.

6. Endocrine effects. The toxicology

database for imidacloprid is current and

complete. Studies in this database

include evaluation of the potential

effects on reproduction and

development, and an evaluation of the

pathology of the endocrine organs

following short or long term exposure.

These studies revealed no primary

endocrine effects due to imidacloprid.

7. Mode of action. Imidacloprid

exhibits a mode of action different from

traditional organophosphate, carbamate,

or pyrethroid insecticides. Imidacloprid

acts by binding to the nicotinergic

receptor sites at the postsynaptic

membrane of the insect nerve. Due to

this novel mode of action, imidacloprid

has not shown any cross resistance to

registered alternative insecticides and is

a valuable tool for use in IPM or

resistance management programs.

D. Aggregate Exposure

Imidacloprid is a broad-spectrum

insecticide with excellent systemic and

contact toxicity characteristics with

both food and non-food uses.

Imidacloprid is currently registered for

use on various food crops including

seed treatments, tobacco, turf,

ornamentals, buildings for termite

control, and cats and dogs for flea

control. Those potential exposures are

addressed below:

1. Dietary. The EPA has determined

that the reference dose (RfD) based on

the 2–year rat feeding/carcinogenicity

study with a NOEL of 5.7 mg/kg/bwt

and hundredfold uncertainty factor, is

calculated to be 0.057 mg/kg/bwt. As

published in the Federal Register June

12, 1996 (61 FR 29674) (petition to

establish tolerances on leafy green

vegetables (PP 5F4522/R2237)), the

theoretical maximum residue

contribution (TMRC) from published

uses is 0.008358 mg/kg/bwt utilizing

14.7 percent of the RfD for the general

population. For the most highly exposed

subgroup in the population, nonnursing infants (less than 1 year old),

the TMRC for the published tolerances

is 0.01547 mg/kg/day. This is equal to

27.1 percent of the RfD.

The TMRC for wheat is calculated to

be 0.000066 mg/kg/bwt/day for the

general population, which represents

0.1 percent of the RfD. The TMRC for

the most highly exposed subgroup in

the population, children 1 to 6 years of

age, is 0.000149 mg/kg/bwt/day, which

represents 0.3 percent of the RfD. The

TMRC for nursing infants is 0.000009

mg/kg/bwt/day, which represents 0.0

percent of the RfD, and for non-nursing

infants is 0.000033 mg/kg/bwt/day,

which represents 0.1 percent of the RfD.

Therefore, dietary exposure from wheat

will not exceed the reference dose for

any subpopulation (including infants

and children).

The TMRC for barley is calculated to

be 0.000004 mg/kg/bwt/day for the

general population, which represents

0.0 percent of the RfD. The TMRC for

the most highly exposed subgroup in

the population, non-nursing infants, is

0.000009 mg/kg/bwt/day, which

represents 0.0 percent of the RfD. The

TMRC for nursing infants is 0.000000

mg/kg/bwt/day, which represents 0.0

percent of the RfD. The TMRC for

children 1 to 6 years of age is 0.000001

mg/kg/bwt/day, which represents 0.0

percent of the RfD. Therefore, dietary

exposure from barley will not exceed

the reference dose for any

subpopulation (including infants and

children).

The TMRC for sugar beets is

calculated to be 0.000012 mg/kg/bwt/

day for the general population, which

represents 0.0 percent of the RfD. The

TMRC for the most highly exposed

subgroup in the population, children 1

to 6 years of age, is 0.000027 mg/kg/

bwt/day, which represents 0.0 percent

of the RfD. The TMRC for non-nursing

infants is 0.000017 mg/kg/bwt/day,

which represents 0.0 percent of the RfD.

The TMRC for nursing infants is

0.000005 mg/kg/bwt/day, which

represents 0.0 percent of the RfD.

Therefore, dietary exposure from sugar

beets will not exceed the reference dose

for any subpopulation (including infants

and children).

The additive TMRC from exposure to

wheat, barley and sugar beets for the

general population, is 0.000082 mg/kg/

bwt/day, which represents 0.1 percent

of the RfD. The additive TMRC from

exposure to wheat, barley and sugar

beets to children, 1 to 6 years of age, is

0.000177 mg/kg/bwt/day, which

represents 0.3 percent of the RfD. For

non-nursing infants, the additive TMRC

is 0.000029 mg/kg/bwt/day, which is 0.1

percent of the RfD. For nursing infants,

the additive TMRC is 0.000014 mg/kg/

bwt/day, which is 0.0 percent of the

RfD.

2. Water. Although the various

imidacloprid labels contain a statement

that this chemical demonstrates the

properties associated with chemicals

detected in groundwater, the Registrant

is not aware of imidacloprid being

detected in any wells, ponds, lakes,

streams, etc. from its use in the United

States. Imidacloprid is hydrolytically

stable at pH 5 and 7 with photolytic

degradation in water having a half-life

of 4.2 hours. Under aerobic soil

conditions in laboratory studies,

imidacloprid has a half-life of 188 to

>366 days. Under laboratory anaerobic

aquatic conditions, the half-life was 27

days. Adsorption/desorption studies

indicate that aged imidacloprid residues

do not leach into the soil. Imidacloprid

dissipates under actual field conditions

with a half-life of 7 to 196 days.

Imidacloprid remained in the top six

inches of the soil in U.S. tests for the

duration of nine of ten field dissipation

studies. The presence of growing

vegetation significantly increased the

rate of degradation of imidacloprid. In

studies conducted in 1995, imidacloprid

was not detected in seventeen wells on

potato farms in Quebec, Canada. In

addition, groundwater monitoring
34268 Federal Register / Vol. 62, No. 122 / Wednesday, June 25, 1997 / Notices

studies are currently underway in

California and Michigan. Therefore,

contributions to the dietary burden from

residues of imidacloprid in water would

be inconsequential.

3. Non-occupational— i. Residential

turf. Bayer Corporation has conducted

an exposure study to address the

potential exposures of adults and

children from contact with imidacloprid

treated turf. The population considered

to have the greatest potential exposure

from contact with pesticide treated turf

soon after pesticides are applied are

young children.

Margins of safety (MOS) of 7,587 -

41,546 for 10 year old children and

6,859 - 45,249 for 5 year old children

were estimated by comparing dermal

exposure doses to the imidacloprid noobservable effect level of 1,000 mg/kg/

day established in a 15–day dermal

toxicity study in rabbits. The estimated

safe residue levels of imidacloprid on

treated turf for 10 year old children

ranged from 5.6 - 38.2 g/cm2 and for 5

year old children from 5.1 - 33.3 g/cm2.

This compares with the average

imidacloprid transferable residue level

of 0.080 g/cm2 present immediately after

the sprays have dried. These data

indicate that children can safely contact

imidacloprid-treated turf as soon after

application as the spray has dried.

ii. Termiticide. Imidacloprid is

registered as a termiticide. Due to the

nature of the treatment for termites,

exposure would be limited to that from

inhalation and was evaluated by EPA’s

Occupational and Residential Exposure

Branch (OREB) and Bayer Corporation.

Data indicate that the Margins of Safety

for the worst case exposures for adults

and infants occupying a treated building

who are exposed continuously (24

hours/day) are 8.0 x 107 and 2.4 x 108,

respectively, and exposure can thus be

considered negligible.

iii. Tobacco smoke. Studies have been

conducted to determine residues in

tobacco and the resulting smoke

following treatment. Residues of

imidacloprid in cured tobacco following

treatment were a maximum of 31 ppm

(7 ppm in fresh leaves). When this

tobacco was burned in a pyrolysis study

only 2 percent of the initial residue was

recovered in the resulting smoke (main

stream plus side stream). This would

result in an inhalation exposure to

imidacloprid from smoking of

approximately 0.0005 mg per cigarette.

Using the measured subacute rat

inhalation NOEL of 5.5 mg/m3, it is

apparent that exposure to imidacloprid

from smoking (direct and/or indirect

exposure) would not be significant.

iv. Pet treatment. Human exposure

from the use of imidacloprid to treat

dogs and cats for fleas has been

addressed by EPA’s Occupational and

Residential Exposure Branch (OREB)

who have concluded that due to the fact

that imidacloprid is not an inhalation or

dermal toxicant and that while dermal

absorption data are not available,

imidacloprid is not considered to

present a hazard via the dermal route.

4. Cumulative Effects. No other

chemicals having the same mechanism

of toxicity are currently registered,

therefore, there is no risk from

cumulative effects from other

substances with a common mechanism

of toxicity.

E. Safety Determinations

1. U.S. Population in general. Using

the conservative exposure assumptions

described above and based on the

completeness and reliability of the

toxicity data, it can be concluded that

total aggregate exposure to imidacloprid

from all current uses including those

currently proposed will utilize little

more than 15 percent of the RfD for the

U.S. population. EPA generally has no

concerns for exposures below 100

percent of the RfD, because the RfD

represents the level at or below which

daily aggregate exposure over a lifetime

will not pose appreciable risks to

human health. The TMRC from

exposure to wheat, barley and sugar

beets for the general population, is

0.000082 mg/kg/bwt/day, which

represents 0.1 percent of the RfD. Thus,

it can be concluded that there is a

reasonable certainty that no harm will

result from aggregate exposure to

imidacloprid residues.

2. Infants and children. In assessing

the potential for additional sensitivity of

infants and children to residues of

imidacloprid, the data from

developmental studies in both rat and

rabbit and a 2–generation reproduction

study in the rat have been considered.

The developmental toxicity studies

evaluate potential adverse effects on the

developing animal resulting from

pesticide exposure of the mother during

prenatal development. The reproduction

study evaluates effects from exposure to

the pesticide on the reproductive

capability of mating animals through 2

generations, as well as any observed

systemic toxicity.

FFDCA Section 408 provides that the

EPA may apply an additional safety

factor for infants and children in the

case of threshold effects to account for

pre- and post-natal effects and the

completeness of the toxicity database.

Based on current toxicological data

requirements, the toxicology database

for imidacloprid relative to pre- and

post-natal effects is complete. Further

for imidacloprid, the NOEL of 5.7 mg/

kg/bwt from the 2–year rat feeding/

carcinogenic study, which was used to

calculate the RfD (discussed above), is

already lower than the NOELs from the

developmental studies in rats and

rabbits by a factor of 4.2 to 17.5 times.

Since a hundredfold uncertainty factor

is already used to calculate the RfD, it

is surmised that an additional

uncertainty factor is not warranted and

that the RfD at 0.057 mg/kg/bwt/day is

appropriate for assessing aggregate risk

to infants and children.

Using the conservative exposure

assumptions described above, EPA has

concluded that the TMRC from use of

imidacloprid from published uses is

0.008358 mg/kg/bwt/day utilizing 14.7

percent of the RfD for the general

population. For the most highly exposed

subgroup in the population, nonnursing infants (less than 1 year old),

the TMRC for the published tolerances

is 0.01547 mg/kg/day. This is equal to

27.1 percent of the RfD. The additive

TMRC from exposure to wheat, barley

and sugar beets to children, 1 to 6 years

of age, is 0.000177 mg/kg/bwt/day,

which represents 0.3 percent of the RfD.

For non-nursing infants, the additive

TMRC is 0.000029 mg/kg/bwt/day,

which is 0.1 percent of the RfD. For

nursing infants, the additive TMRC is

0.000014 mg/kg/bwt/day, which is 0.0

percent of the RfD. Thus, it can be

concluded that there is a reasonable

certainty that no harm will result from

additional exposure of infants and

children.

F. Other Considerations

The nature of the imidacloprid

residue in plants and livestock is

adequately understood. The residues of

concern are combined residues of

imidacloprid and its metabolites

containing the 6-chloropyridinyl

moiety, all calculated as imidacloprid.

The analytical method is a common

moiety method for imidacloprid and its

metabolites containing the 6-

chloropyridinyl moiety using a

permanganate oxidation, silyl

derivatization, and capillary GC-MS

selective ion monitoring. There is an

additional confirmatory method

available. Imidacloprid and its

metabolites have been shown to be

stable for at least 24 months in frozen

storage.

G. International Tolerances

No CODEX Maximum Residue Levels

(MRLs) have been established for

residues of imidacloprid on any crops at

this time.
Federal Register / Vol. 62, No. 122 / Wednesday, June 25, 1997 / Notices 34269

3. Gustafson Incorporation

PP 6F4682

EPA has received a pesticide petition

(PP 6F4682) pursuant to section 408(d)

of the Federal Food, Drug and Cosmetic

Act, as amended, 21 U.S.C. 346a(d), by

the Food Quality Protection Act of 1996

(Pub. L. 104-170, 110 Stat. 1489) from

Gustafson, Inc., 1400 Preston Road,

Suite 400, Plano, Texas 75093

requesting that tolerances be established

for residues of the insecticide,

imidacloprid: 1-[(6-chloro-3-

pyridinyl)methyl]-N-nitro-2-

imidazolidinimine and its metabolites

containing the 6-chloro-pyridinyl

moiety. It is proposed that tolerances of

0.05 parts per million (ppm) for field

corn, grain, 0.02 ppm for field corn,

fodder and 0.10 ppm for field corn,

forage be established. The nature of the

imidacloprid residue in plants and

livestock is adequately understood. The

analytical method for determining

residues is a common moiety method

for imidacloprid and its metabolites

containing the 6-chloro-pyridinyl

moiety using oxidation, derivatization,

and analysis by capillary gas

chromatography with a mass-selective

detector.

Imidacloprid is a broad spectrum

insecticide with excellent systemic and

contact toxicity characteristics which is

used primarily for sucking insects.

Pursuant to section 408(d)(2)(A)(i) of the

FFDCA, as amended, Gustafson has

submitted the following summary of

information, data and arguments in

support of its pesticide petition. The

summary was proposed by Gustafson,

and EPA has not yet fully evaluated the

merits of the petition. The conclusions

and arguments presented are those of

the petitioner and not of the EPA

although the EPA has edited the

summary for clarification as necessary.

A. Plant Metabolism and Analytical

Method

The metabolism of imidacloprid in

plants is adequately understood for the

purposes of these tolerances. The

residues of concern are combined

residues of imidacloprid and its

metabolites containing the 6-chloropyridinyl moiety, all calculated as

imidacloprid. The analytical method is

a common moiety method for

imidacloprid and its metabolites

containing the 6-chloro-pyridinyl

moiety using a permanganate oxidation,

silyl derivatization, and capillary GCMS selective ion monitoring. This

method has successfully passed a

petition method validation in EPA labs.

There is a confirmatory method

specifically for imidacloprid and several

metabolites utilizing GC/MS and HPLCUV which has been validated by the

EPA as well. Imidacloprid and its

metabolites are stable for at least 24

months in the commodities when

frozen.

B. Magnitude of the Residue

Corn seed was treated with

imidacloprid, formulated as Gaucho 480

FS at a rate of 8.0 oz.ai/cwt seed. Field

trials were conducted at twenty

locations, one in Region 1, one in

Region 2, seventeen in Region 5, and

one in Region 6. The corn seed was

planted and the RACs were harvested at

the appropriate growth stages. The

highest average residue level found in

field corn forage was 0.064 ppm. The

highest average residue level found in

the field corn grain was less than the

Limit of Quantitation, which was 0.05

ppm. The highest average residue level

found in the field corn fodder was 0.150

ppm. The proposed tolerance for field

corn forage is 0.10 ppm. The proposed

tolerance for the field corn fodder is

0.20 ppm. The proposed tolerance for

the field corn grain is 0.05 ppm.

Since there were no quantifiable

residues in the field corn grain RAC

samples analyzed in the processing

study or in the RAC study, neither a

section 409 food/feed additive tolerance

or a section 701 maximum residue level

is required for the processed

commodities.

C. Toxicological Profile of Imidacloprid

1. Acute toxicity. The acute oral LD50

values for imidacloprid technical ranged

from 424 - 475 mg/kg bwt in the rat. The

acute dermal LD50 was greater than

5,000 mg/kg in rats. The 4 hour

inhalation LC50 was less than 69 mg/m3

air (aerosol). Imidacloprid was not

irritating to rabbit skin or eyes.

Imidacloprid did not cause skin

sensitization in guinea pigs.

2. Genotoxicity. Extensive

mutagenicity studies conducted to

investigate point and gene mutations,

DNA damage and chromosomal

aberration, both using in vitro and in

vivo test systems show imidacloprid to

be non-genotoxic.

3. Reproductive and developmental

toxicity. A 2–generation rat

reproduction study gave a no-observedeffect level (NOEL) of 100 ppm (8 mg/

kg/bwt). Rat and rabbit developmental

toxicity studies were negative at doses

up to 30 mg/kg/bwt and 24 mg/kg/bwt,

respectively.

4. Subchronic toxicity. 90–day feeding

studies were conducted in rats and

dogs. The NOELs for these tests were 14

mg/kg/bwt/day (150 ppm) and 5 mg/kg/

bwt/day (200 ppm), for the rat and dog

studies, respectively.

5. Chronic toxicity/oncogenicity. A 2–

year rat feeding/ carcinogenicity study

was negative for carcinogenic effects

under the conditions of the study and

had a NOEL of 100 ppm (5.7 mg/kg/bwt

in males and 7.6 mg/kg/bwt in females

for noncarcinogenic effects that

included decreased body weight gain in

females at 300 ppm and increased

thyroid lesions in males at 300 ppm and

females at 900 ppm. A 1–year dog

feeding study indicated a NOEL of 1,250

ppm (41 mg/kg/bwt). A 2–year mouse

carcinogenicity study was negative for

carcinogenic effects under conditions of

the study and had a NOEL of 1,000 ppm

(208 mg/kg/day).

Imidacloprid has been classified

under ‘‘Group E’’ (no evidence of

carcinogenicity) by EPA’s OPP/HED’s

Reference Dose (RfD) Committee. There

is no cancer risk associated with

exposure to this chemical. The reference

dose (RfD) based on the 2–year rat

feeding/carcinogenic study with a NOEL

of 5.7 mg/kg/bwt and hundredfold

uncertainty factor, is calculated to be

0.057 mg/kg/bwt. The theoretical

maximum residue contribution (TMRC)

from published uses is 0.008358 mg/kg/

bwt/day utilizing 14.7 percent of the

RfD.

6. Endocrine effects. The toxicology

database for imidacloprid is current and

complete. Studies in this database

include evaluation of the potential

effects on reproduction and

development, and an evaluation of the

pathology of the endocrine organs

following short or long term exposure.

These studies revealed no primary

endocrine effects due to imidacloprid.

7. Mode of action. Imidacloprid

exhibits a mode of action different from

traditional organophosphate, carbamate,

or pyrethroid insecticides. Imidacloprid

acts by binding to the nicotinergic

receptor sites at the postsynaptic

membrane of the insect nerve. Due to

this novel mode of action, imidacloprid

has not shown any cross resistance to

registered alternative insecticides and is

a valuable tool for use in IPM or

resistance management programs.

D. Aggregate Exposure

Imidacloprid is a broad-spectrum

insecticide with excellent systemic and

contact toxicity characteristics with

both food and non-food uses.

Imidacloprid is currently registered for

use on various food crops including

seed treatments, tobacco, turf,

ornamentals, buildings for termite

control, and cats and dogs for flea

control. Those potential exposures are

addressed below:
34270 Federal Register / Vol. 62, No. 122 / Wednesday, June 25, 1997 / Notices

1. Dietary. The EPA has determined

that the reference dose (RfD) based on

the 2–year rat feeding/carcinogenicity

study with a NOEL of 5.7 mg/kg/bwt

and hundredfold uncertainty factor, is

calculated to be 0.057 mg/kg/bwt. As

published in the Federal Register June

12, 1996 (61 FR 29674) (petition to

establish tolerances on leafy green

vegetables (PP 5F4522/R2237), the

theoretical maximum residue

contribution (TMRC) from published

uses is 0.008358 mg/kg/bwt utilizing

14.7 percent of the RfD for the general

population. For the most highly exposed

subgroup in the population, nonnursing infants (less than 1 year old),

the TMRC for the published tolerances

is 0.01547 mg/kg/day. This is equal to

27.1 percent of the RfD.

The TMRC for corn is calculated to be

0.000055 mg/kg/bwt/day for the general

population, which represents 0.1

percent of the RfD. The TMRC for the

most highly exposed subgroup in the

population, non-nursing infants is

0.000131 mg/kg/bwt/day, which

represents 0.2 percent of the RfD. The

TMRC for children ages 1 to 6 years is

0.000130 mg/kg/bwt/day, which

represents 0.2 percent of the RfD, and

for nursing infants is 0.000032 mg/kg/

bwt/day, which represents 0.1 percent

of the RfD. For children 7 to 12 years of

age, the TMRC is 0.000098 mg/kg/bwt/

day, which represents 0.2 percent of the

RfD. Therefore, dietary exposure from

field corn will not exceed the reference

dose for any subpopulation (including

infants and children).

2. Water. Although the various

imidacloprid labels contain a statement

that this chemical demonstrates the

properties associated with chemicals

detected in groundwater, the Registrant

is not aware of imidacloprid being

detected in any wells, ponds, lakes,

streams, etc. from its use in the United

States. Imidacloprid is hydrolytically

stable at pH 5 and 7 with photolytic

degradation in water having a half-life

of 4.2 hours. Under aerobic soil

conditions in laboratory studies,

imidacloprid has a half-life of 188 to

>366 days. Under laboratory anaerobic

aquatic conditions, the half-life was 27

days. Adsorption/desorption studies

indicate that aged imidacloprid residues

do not leach into the soil. Imidacloprid

dissipates under actual field conditions

with a half-life of 7 to 196 days.

Imidacloprid remained in the top six

inches of the soil in U.S. tests for the

duration of nine of ten field dissipation

studies. The presence of growing

vegetation significantly increased the

rate of degradation of imidacloprid. In

studies conducted in 1995, imidacloprid

was not detected in seventeen wells on

potato farms in Quebec, Canada. In

addition, groundwater monitoring

studies are currently underway in

California and Michigan. Therefore,

contributions to the dietary burden from

residues of imidacloprid in water would

be inconsequential.

3. Non-occupational— i. Residential

turf. Bayer Corporation has conducted

an exposure study to address the

potential exposures of adults and

children from contact with imidacloprid

treated turf. The population considered

to have the greatest potential exposure

from contact with pesticide treated turf

soon after pesticides are applied are

young children.

Margins of safety (MOS) of 7,587 -

41,546 for 10 year old children and

6,859 - 45,249 for 5 year old children

were estimated by comparing dermal

exposure doses to the imidacloprid noobservable effect level of 1,000 mg/kg/

day established in a 15 day dermal

toxicity study in rabbits. The estimated

safe residue levels of imidacloprid on

treated turf for 10 year old children

ranged from 5.6 - 38.2 g/cm2 and for 5

year old children from 5.1 - 33.3 g/cm2.

This compares with the average

imidacloprid transferable residue level

of 0.080 g/cm2 present immediately after

the sprays have dried. These data

indicate that children can safely contact

imidacloprid-treated turf as soon after

application as the spray has dried.

ii. Termiticide. Imidacloprid is

registered as a termiticide. Due to the

nature of the treatment for termites,

exposure would be limited to that from

inhalation and was evaluated by EPA’s

Occupational and Residential Exposure

Branch (OREB) and Bayer Corporation.

Data indicate that the Margins of Safety

for the worst case exposures for adults

and infants occupying a treated building

who are exposed continuously (24

hours/day) are 8.0 x 107 and 2.4 x 108,

respectively, and exposure can thus be

considered negligible.

iii. Tobacco smoke. Studies have been

conducted to determine residues in

tobacco and the resulting smoke

following treatment. Residues of

imidacloprid in cured tobacco following

treatment were a maximum of 31 ppm

(7 ppm in fresh leaves). When this

tobacco was burned in a pyrolysis study

only two percent of the initial residue

was recovered in the resulting smoke

(main stream plus side stream). This

would result in an inhalation exposure

to imidacloprid from smoking of

approximately 0.0005 mg per cigarette.

Using the measured subacute rat

inhalation NOEL of 5.5 mg/m3, it is

apparent that exposure to imidacloprid

from smoking (direct and/or indirect

exposure) would not be significant.

iv. Pet treatment. Human exposure

from the use of imidacloprid to treat

dogs and cats for fleas has been

addressed by EPA’s Occupational and

Residential Exposure Branch (OREB)

who have concluded that due to the fact

that imidacloprid is not an inhalation or

dermal toxicant and that while dermal

absorption data are not available,

imidacloprid is not considered to

present a hazard via the dermal route.

4. Cumulative effects. No other

chemicals having the same mechanism

of toxicity are currently registered,

therefore, there is no risk from

cumulative effects from other

substances with a common mechanism

of toxicity.

E. Safety Determinations

1. U.S. Population in general. Using

the conservative exposure assumptions

described above and based on the

completeness and reliability of the

toxicity data, it can be concluded that

total aggregate exposure to imidacloprid

from all current uses including those

currently proposed will utilize little

more than 15 percent of the RfD for the

U.S. population. EPA generally has no

concerns for exposures below 100

percent of the RfD, because the RfD

represents the level at or below which

daily aggregate exposure over a lifetime

will not pose appreciable risks to

human health. The TMRC from

exposure to field corn for the general

population, is 0.000055 mg/kg/bwt/day,

which represents 0.1 percent of the RfD.

Thus, it can be concluded that there is

a reasonable certainty that no harm will

result from aggregate exposure to

imidacloprid residues.

2. Infants and children. In assessing

the potential for additional sensitivity of

infants and children to residues of

imidacloprid, the data from

developmental studies in both rat and

rabbit and a 2–generation reproduction

study in the rat have been considered.

The developmental toxicity studies

evaluate potential adverse effects on the

developing animal resulting from

pesticide exposure of the mother during

prenatal development. The reproduction

study evaluates effects from exposure to

the pesticide on the reproductive

capability of mating animals through 2

generations, as well as any observed

systemic toxicity.

FFDCA section 408 provides that the

EPA may apply an additional safety

factor for infants and children in the

case of threshold effects to account for

pre- and post-natal effects and the

completeness of the toxicity database.

Based on current toxicological data

requirements, the toxicology database

for imidacloprid relative to pre- and
Federal Register / Vol. 62, No. 122 / Wednesday, June 25, 1997 / Notices 34271

post-natal effects is complete. Further

for imidacloprid, the NOEL of 5.7 mg/

kg/bwt from the 2–year rat feeding/

carcinogenic study, which was used to

calculate the RfD (discussed above), is

already lower than the NOELs from the

developmental studies in rats and

rabbits by a factor of 4.2 to 17.5 times.

Since a hundredfold uncertainty factor

is already used to calculate the RfD, it

is surmised that an additional

uncertainty factor is not warranted and

that the RfD at 0.057 mg/kg/bwt/day is

appropriate for assessing aggregate risk

to infants and children. Using the

conservative exposure assumptions

described above, EPA has concluded

that the TMRC from use of imidacloprid

from published uses is 0.008358 mg/kg/

bwt/day utilizing 14.7 percent of the

RfD for the general population. For the

most highly exposed subgroup in the

population, non-nursing infants (less

than 1 year old), the TMRC for the

published tolerances is 0.01547 mg/kg/

day. This is equal to 27.1 percent of the

RfD. The TMRC from exposure to field

corn to non-nursing infants is 0.000131

mg/kg/bwt/day, which represents 0.2

percent of the RfD. The TMRC for

children ages 1 to 6 years is 0.000130

mg/kg/bwt/day, which represents 0.2

percent of the RfD. For nursing infants,

the TMRC is 0.000032 mg/kg/bwt/day,

which is 0.1 percent of the RfD. For

children ages 7 to 12 years, the TMRC

is 0.000098 mg/kg/bwt/day, which is 0.2

percent of the RfD. Thus, it can be

concluded that there is a reasonable

certainty that no harm will result from

additional exposure of infants and

children.

F. Other Considerations

The nature of the imidacloprid

residue in plants and livestock is

adequately understood. The residues of

concern are combined residues of

imidacloprid and its metabolites

containing the 6-chloropyridinyl

moiety, all calculated as imidacloprid.

The analytical method is a common

moiety method for imidacloprid and its

metabolites containing the 6-

chloropyridinyl moiety using a

permanganate oxidation, silyl

derivatization, and capillary GC-MS

selective ion monitoring. There is an

additional confirmatory method

available. Imidacloprid and its

metabolites have been shown to be

stable for at least 24 months in frozen

storage.

G. International Tolerances

No CODEX Maximum Residue Levels

(MRLs) have been established for

residues of imidacloprid on any crops at

this time.

[FR Doc. 97–16655 Filed 6–24–97; 8:45 am]

BILLING CODE 6560–50–F

ENVIRONMENTAL PROTECTION

AGENCY

[PF–739; FRL–5721–7]

Notice of Filing of Pesticide Petitions

AGENCY: Environmental Protection

Agency (EPA).

ACTION: Notice.

SUMMARY: This notice announces the

initial filing of pesticide petitions

proposing the establishment of

regulations for residues of certain

pesticide chemicals in or on various

food commodities.

DATES: Comments, identified by the

docket control number PF–739, must be

received on or before July 25, 1997.

ADDRESSES: By mail submit written

comments to: Public Information and

Records Integrity Branch, Information

Resources and Services Division

(7506C), Office of Pesticides Programs,

Environmental Protection Agency, 401

M St., SW., Washington, DC 20460. In

person bring comments to: Rm. 1132,

CM #2, 1921 Jefferson Davis Highway,

Arlington, VA.

Comments and data may also be

submitted electronically by following

the instructions under

‘‘SUPPLEMENTARY INFORMATION.’’

No confidential business information

should be submitted through e-mail.

Information submitted as a comment

concerning this document may be

claimed confidential by marking any

part or all of that information as

‘‘Confidential Business Information’’

(CBI). CBI should not be submitted

through e-mail. Information marked as

CBI will not be disclosed except in

accordance with procedures set forth in

40 CFR part 2. A copy of the comment

that does not contain CBI must be

submitted for inclusion in the public

record. Information not marked

confidential may be disclosed publicly

by EPA without prior notice. All written

comments will be available for public

inspection in Rm. 1132 at the address

given above, from 8:30 a.m. to 4 p.m.,

Monday through Friday, excluding legal

holidays.

FOR FURTHER INFORMATION CONTACT: The

regulatory action leaders listed in the

table below:

Product Manager Office location/telephone number Address

Sheryl Reilly (PM 90) ..... Rm. 5-W29, 5th Floor, CS-1, 703-308-8265 e-mail: reilly.sheryl@epamail.epa.gov 2800 Jefferson Davis Hwy., Arlington, VA 22202

Mike Mendelsohn (PM

90).

Rm. 5-W44, 5th Floor, CS-1, 703-308-8715 e-mail:

mendelsohn.mike@epamail.epa.gov

Do.

Linda Hollis (PM 90) ...... Rm 5-J, 5th Floor, CS-1, 703-308-8733 e-mail: hollis.linda@epamail.epa.gov Do.

SUPPLEMENTARY INFORMATION: EPA has

received pesticide petitions as follows

proposing the establishment and/or

amendment of regulations for residues

of certain pesticide chemicals in or on

various food commodities under section

408 of the Federal Food, Drug, and

Comestic Act (FFDCA), 21 U.S.C. 346a.

EPA has determined that these petitions

contain data or information regarding

the elements set forth in section

408(d)(2); however, EPA has not fully

evaluated the sufficiency of the

submitted data at this time or whether

the data supports granting of the

petition. Additional data may be needed

before EPA rules on the petition.

The official record for this notice of

filing, as well as the public version, has

been established for this notice of filing

under docket control number [PF–739]

(including comments and data

submitted electronically as described

below). 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 official

record is located at the address in

‘‘ADDRESSES’’ at the beginning of this

document.

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. Comment and data will

also be accepted on disks in