[Federal Register Volume 62, Number 168 (Friday, August 29, 1997)]
[Notices]
[Pages 45804-45810]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-23097]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-758; FRL-5738-2]


Notice of Filing of Pesticide Petitions

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

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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-758, must 
be received on or before September 29, 1997.
ADDRESSES: By mail submit written comments to: Public Information and 
Records Integrity Branch (7506C), Information Resources and Services 
Division, 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 contact person listed in the table 
below:

[[Page 45805]]



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                                   Office location/                     
        Contact Person             telephone number          Address    
------------------------------------------------------------------------
Beth Edwards,.................  Rm. 211, CM #2, 703-    1921 Jefferson  
                                 305-5400, e-            Davis Hwy,     
                                 mail:edwards.beth@epa   Arlington, VA  
                                 mail.epa.gov.                          
Amelia Acierto................  4th floor, CS1, 703-    2800 Crystal    
                                 308-8377, e-mail:       Drive,         
                                 acierto.amelia@epamai   Arlington, VA. 
                                 l.epa.gov.                             
Bipin Gandhi,.................  Rm.4W53, CS1, 703-308-  Do.             
                                 8380, e-mail:                          
                                 gandhi.bipin@epamail.
epa.gov.                               
------------------------------------------------------------------------

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-758] (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:
    [email protected]


    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-758] 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: August 20, 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. American Cyanamid Company

PP 3E4246

    EPA has received a pesticide petition (PP 3E4246) from American 
Cyanamid Company, Agricultural Products Research Division, P.O. Box 
400, Princeton, NJ 08543-0400, proposing pursuant to section 408(d) of 
the Federal Food, Drug and Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 
CFR part 180 to establish an exemption from the requirement of a 
tolerance for residues of Polyvinyl Chloride (PVC) when used as an 
inert ingredient in pesticide formulations applied to growing crops or 
to raw agricultural commodities after harvest, under 40 CFR 
180.1001(c). EPA has determined that the petition contains data or 
information regarding the elements set forth in section 408(d)(2) of 
the FFDCA; 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.

A. Toxicity Data

    As part of the EPA policy statement on inert ingredients published 
in the Federal Register of April 22, 1987 (52 FR 13305), the Agency set 
forth a list of studies which would generally be used to evaluate the 
risks posed by the presence of an inert ingredient in a pesticide 
formulation. However, where it can be determined without the data that 
the inert ingredient will present minimal or no risk, the Agency 
generally does not require some or all of the listed studies to rule on 
the proposed tolerance or exemption from the requirement of a tolerance 
for an inert ingredient. Cyanamid believes that the data and 
information described below is adequate to ascertain the toxicology and 
characterize the risk associated with the use of PVC as an inert 
ingredient in pesticide formulations applied to growing crops and raw 
agricultural commodities after harvest.
    In the case of certain chemical substances that are defined as 
``polymers'', the EPA has established a set of criteria which identify 
categories of polymers that present low risk. These criteria (described 
in 40 CFR 723.250) identify polymers that are relatively unreactive and 
stable compared to other chemical substances as well as polymers that 
typically are not readily absorbed. These properties generally limit a 
polymer's ability to cause adverse effects. In addition, these criteria 
exclude polymers about which little is known. The EPA believes that 
polymers meeting the criteria noted below will present minimal or no 
risk.
    Polyvinyl chloride (PVC) conforms to the definition of polymer 
given in 40 CFR 723.250(b) and meets the following criteria that are 
used to identify low risk polymers:
    1. PVC is not a cationic polymer, nor is it reasonably anticipated 
to become a cationic polymer in a natural aquatic environment.
    2. PVC contains as an integral part of its composition the atomic 
elements carbon, chlorine, and hydrogen.
    3. PVC does not contain as an integral part of its composition, 
except as impurities, any elements other than those listed in 40 CFR 
723.250 (d)(2)(ii).
    4. PVC is not designed, nor is it reasonably anticipated to 
substantially degrade, decompose, or depolymerize.
    5. PVC is not manufactured or imported from monomers and/or other 
reactants that are not already included on the Toxic Substance Control 
Act (TSCA) Chemical Substance Inventory or manufactured under an 
applicable TSCA section 5 exemption.
    6. PVC is not a water absorbing polymer.

[[Page 45806]]

    7. PVC does not contain any group as reactive functional groups.
    8. The minimum number-average molecular weight of PVC is listed as 
29,000 daltons. Substances with molecular weights greater than 400 
generally are not absorbed through the intact skin, and substances with 
molecular weights greater than 1,000 generally are not absorbed through 
the intact gastrointestinal (GI) tract. Chemicals not absorbed through 
the skin or GI tract generally are incapable of eliciting a toxic 
response.
    9. PVC has a minimum number-average molecular weight of 29,000 and 
contains less than 2 percent oligomeric material below molecular weight 
500 and less than 5 percent oligomeric material below 1,000 molecular 
weight.
    In addition, PVC is approved by the Food and Drug Administration 
(FDA) under 21 CFR for contact with food as a component in adhesives 
(21 CFR 175.105), coatings (21 CFR 175.320), and paper and paperboard 
(21 CFR 176.180). PVC is also approved by FDA as an indirect food 
additive used as a basic component of acrylic (21 CFR 177.1010) and 
cellophane (21 CFR 177.1200) polymers.
    PVC is also cleared for use as water pipe for potable water as per 
FFDCA 201(s).

B. Aggregate Exposure

    PVC was one of the earliest and still most widely used plastics. 
The polymer is ubiquitous in our every day environment as it is 
commonly used in building materials, furniture, and textiles. It is 
also cleared by FDA as an indirect food additive due to its use in food 
packaging materials.
    Although exposure to PVC may occur through dietary (e.g., PVC-
containing food wrapping), non-occupational (e.g., contact with PVC 
furniture), and drinking water (e.g., potable water piping, water 
bottles, etc.) sources, the chemical characteristics of PVC lead to the 
conclusion that there is a reasonable certainty of no harm from 
aggregate exposure to the polymer. Given the existing widespread use of 
PVC, any additional exposure resulting from the approval of the use of 
PVC as an inert ingredient in pesticide formulations for use on growing 
crops or to raw agricultural commodities after harvest would be 
trivial.

C. Cumulative Effects

    At this time there is no information to indicate that any toxic 
effects produced by PVC would be cumulative with those of any other 
chemical. Given the compound's categorization as a ``low risk polymer'' 
(40 CFR 723.250) and its proposed used as an inert ingredient in 
pesticide formulations, there is no reasonable expectation of increased 
risk due to cumulative exposure to PVC.

D. International Tolerances

    Cyanamid is petitioning that PVC be exempt from the requirement of 
a tolerance based upon its status as a low risk polymer as per 40 CFR 
723.250. Therefore, an analytical method to determine residues of PVC 
in raw agricultural commodities treated with pesticide formulations 
containing PVC has not been proposed.
    There are no Codex maximum residue levels (MRLs) established for 
PVC.
     Residues of PVC are currently exempt from the requirement of a 
tolerance under 40 CFR 180.1001(e) for use in pesticide formulations 
applied to animals. (Bipin Gandhi)

2. Merck Research Laboratories, Inc. (Merck)

PP 7F4845

    EPA has received a pesticide petition (PP 7F4845) from Merck 
Research Laboratories, Inc. (Merck), P.O. Box 450, Hillsborough Road, 
Three Bridges, NJ 08887-0450, proposing pursuant to section 408(d) of 
the Federal Food, Drug and Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 
CFR part 180 by establishing tolerances for residues of emamectin 
benzoate and certain of its degradates in or on the fruiting vegetables 
crop group (except cucurbits), which includes the raw agricultural 
commodities eggplants, groundcherries, pepinos, peppers (bell, chili, 
cooking, and sweet), tomatillos, and tomatoes. Emamectin benzoate is a 
new insecticide designed for use against the larvae of various 
Lepidoptera species when applied in the form of an emulsifaiable 
concentrate formulation (PROCLAIM 0.16 EC Insecticide) or a 
soluble granular formulation (PROCLAIM 5% SG Insecticide).
    Merck Research Laboratories, Inc. (Merck) previously has applied 
for the registration under section 3 of the Federal Insecticide, 
Fungicide, and Rodenticide Act (FIFRA) of three products containing 
emamectin benzoate: emamectin benzoate technical (EPA File Symbol 618-
RNI); PROCLAIM 0.16 EC Insecticide (EPA File Symbol 618-RNT); and 
PROCLAIM 5% SG Insecticide (EPA File Symbol 618-RNA). Notice of filing 
of these applications was published in the Federal Register on July 10, 
1996 (61 FR 36372). In the previous petition, Merck proposed that the 
end-use products be registered for use on broccoli, Brussels sprouts, 
cabbage, cauliflower, celery, and head lettuce. Merck has also 
submitted a petition under section 408 of the Federal Food, Drug, and 
Cosmetic Act (FFDCA) for the establishment of permanent tolerances for 
residues of emamectin benzoate on the raw agricultural commodities 
(RACs) broccoli, Brussels sprouts, cabbage, cauliflower, celery, and 
head lettuce. EPA has assigned this petition the number PP 6F4628.
    Merck is now submitting this new petition for the issuance of a 
tolerance for residues of emamectin on the ``fruiting vegetables 
(except cucurbits)'' crop group, which includes eggplants, 
groundcherriees, pepinos, peppers (bell, chili, cooking, and sweet), 
tomatillos, and tomatoes.
    The tolerances sought are for the total toxic residue, consisting 
of the parent insecticide (emamectin benzoate) and four other 
components that are plant metabolites or photodegradation products. For 
each RAC the proposed tolerance level is 0.02 ppm. The pesticide 
chemical that produces such residues is the parent insecticide 
emamectin benzoate. Further information on the chemical identity and 
composition of these compounds is set forth in the EPA files for the 
three applications discussed in the previous paragraph above.

A. Residue Chemistry

    1. Plant metabolism. The metabolism of emamectin benzoate in plants 
has been studied in lettuce, cabbage, and sweet corn. The major portion 
of the residue is parent compound and its delta 8,9- photoisomer. 
Studies of the metabolism of emamectin in animals are not required 
because the commodities that are the subject of the petition are not 
significant animal feed items.
    2. Analytical method. Adequate analytical methods (HPLC-
fluorescence methods) are available for enforcement purposes.
    3. Magnitude of residues. Twenty-three field trials have been 
conducted: 11 on peppers and 12 on tomatoes. A processing study was 
also carried out with tomatoes. These trials were conducted in the 
major U.S. growing areas for these crops.
    All trials were conducted under maximum proposed use rates and 
conditions. Raw agricultural commodity (RAC) samples from all trials 
were collected a few hours after the last treatment (day 0) and on days 
3, 7, and 14. In one trial samples were also collected for use in a 
processing study.
    In day 7 (and later) whole tomato samples, the highest level of the 
B1a component and of the n-formyl component were each NQ (not 
quantifiable, less than 5 ng/g); for the

[[Page 45807]]

other two components the residues were less than 1 ng/g. In day 7 (and 
later) pepper samples, the highest B1a residue was 5 ng/g , the highest 
n-formyl residue was NQ (less than 5 ng/g), and the other two 
components were less than 1 ng/g in each sample. Thus, the maximum 
combined residue was less than 12 ng/g (less than 0.012 ppm) in each 
case. The processing study showed that the residues did not concentrate 
in tomato puree or paste.
    These data support the proposed tolerance of 0.02 ppm for total 
toxic residues of emamectin benzoate on tomatoes, tomato puree, tomato 
paste, or peppers, and by extension to remaining members of the 
fruiting vegetables (except cucurbits) group.

B. Toxicological Profile

    The primary toxic effect seen in animal studies of emamectin 
benzoate is neurotoxicity. No-observed-effect-levels (NOELs) for this 
effect have been well characterized in multiple studies. Emamectin 
benzoate has not been shown to be oncogenic or teratogenic in animal 
studies, it lacks mutagenic activity, and it is not selectively 
developmentally toxic. The petition refers to toxicity data that 
establish the following information about the toxicity of emamectin 
benzoate:
    1. Acute toxicity. Acute oral LD50: rat, 76-89 mg/kg; 
CD-1 mouse 107-120 mg/kg; CF-1 mouse, 22-31 mg/kg. Acute oral 
neurotoxicity: rat, NOEL = 5 mg/kg, LOEL = 10 mg/kg. Acute dermal 
LD50: rat and rabbit, >2,000 mg/kg. Dermal irritation: 
rabbit, not irritating to skin. Eye irritation: rabbit, severe eye 
irritant. Acute inhalation 4-hour LC50: rat, 2.12-4.44 mg/l.
    2. Mutagenicity. Emamectin benzoate was tested in a battery of in 
vitro and in vivo mutagenicity assays and showed no evidence of 
mutagenic potential. The photodegradates have also been tested in the 
Ames bacterial mutagenicity assay and show no mutagenic potential in 
this test system.
    3. Reproductive and developmental toxicity. Developmental toxicity: 
rat, maternal NOEL = 2 mg/kg/day, developmental NOEL = 4 mg/kg/day, 
developmental LOEL = maternally toxic 8 mg/kg/day (HDT) for 
developmental delay; rabbit, maternal NOEL = 3 mg/kg/day, developmental 
NOEL = 6 mg/kg/day (maternally toxic HDT). Developmental neurotoxicity: 
rat, maternal NOEL = 3.6/2.5 mg/kg/day (HDT), developmental NOEL = 0.6 
mg/kg/day, developmental LOEL = 3.6/2.5 mg/kg/day for signs of 
neurotoxicity in pups. 2-generation reproductive toxicity: rat, 
parental and reproductive NOEL = 0.6 mg/kg/day, parental LOEL = 3.6/1.8 
mg/kg/day (for decreased weight gain and neuronal lesions); 
reproductive toxicity LOEL = 3.6/1.8 mg/kg/day (for decreased fecundity 
and signs of neurotoxicity in pups).
    4. Subchronic and chronic toxicity and oncogenicity. With the 
single exception of the chronic rat study, LOELs for the following 
studies are based on clinical signs and/or histopathological evidence 
of neurotoxicity (described further below). Subchronic (90-day) 
toxicity: rat, NOEL = 0.5 mg/kg/day, LOEL = 2.5 mg/kg/day; CD-1 mouse, 
NOEL = 5.4 mg/kg/day (TWA), LOEL = 0.5 mg/kg/day; dog, NOEL = 0.25 mg/
kg/day, LOEL = 0.5 mg/kg/day Subchronic (90-day) neurotoxicity; rat, 
NOEL = 1 mg/kg/day, LOEL = 5 mg/kg/day. Chronic (105-week) toxicity/
oncogenicity, rat: NOEL = 0.25 mg/kg/day, LOEL = 1 mg/kg/day (based on 
decreased body weight and clinical chemistry changes), neurotoxicity 
NOEL = 1 mg/kg/day, not oncogenic. Chronic (79-week) toxicity/
oncogenicity, CD-1 mouse: NOEL = 2.5 mg/kg/day, LOEL = 5 mg/kg (males), 
7.5 mg/kg/day (females), not oncogenic. Chronic (53-week) toxicity, 
dog: NOEL = 0.25 mg/kg/day, LOEL= 0.5 mg/kg./day.
    Exposure to sufficiently high doses of emamectin benzoate may be 
associated with clinical signs of central nervous system (CNS) toxicity 
and microscopic evidence of CNS/peripheral nervous system (PNS) damage. 
Neurotoxicity has generally been the most sensitive endpoint for 
toxicity in oral animal studies with emamectin benzoate. Clinical signs 
of CNS toxicity resulting from emamectin benzoate exposure include 
tremors, mydriasis, and changes in motor activity (e.g., lethargy, 
hyperactivity, and/or ataxia). Nervous system lesions (generally focal 
and of a low degree of severity) have been observed microscopically in 
white and gray matter in the brain stem, spinal cord, and peripheral 
nerves. Sporadic lesions of the optic nerve and/or retina have also 
been seen at higher dose levels. NOELs have been determined in all 
studies. The lowest toxic dose level of emamectin benzoate for CNS/PNS 
lesions (0.5 mg/kg/day) was identified in a 1-year study in dogs (NOEL 
of 0.25 mg/kg/day).
    The CF-l mouse is uniquely sensitive to emamectin benzoate-induced 
neurotoxicity. Studies have shown that a significant fraction of the 
members of this strain inherit an inability to produce a P-
glycoprotein- one that most strains and species do produce- that 
functions to resist the entrance of avermectin-type compounds into the 
central nervous system. P-glycoprotein is also present in the gut of 
most species and limits absorption of avermectin-type compounds 
following oral exposure. In a 16-day feeding study in the CF-1 mouse, 
tremors were seen at 0.3 mg/kg/day of emamectin benzoate with a NOEL of 
0.1 mg/kg/day. No histopathologic evidence of neurotoxicity was seen in 
this study up to the highest dose tested (0.9 mg/kg/day).
    Emamectin benzoate photodegrades on plants and in soil. The major 
photodegradates that are not animal metabolites were tested in a 15-day 
neurotoxicity study in CF-1 mice. Only one photodegradate showed 
neurotoxicity (Merck research number L-660,599, the N-formyl-N-methyl 
degradate). Its NOEL was found to be 0.075 mg/kg/day, slightly lower 
than the value for the parent compound in the same kind of study, and 
both clinical signs and peripheral nerve lesions were observed at 
levels of 0.1 mg/kg/day and higher.
    5. Endpoint selection. Merck is proposing that the 0.075 mg/kg/day 
NOEL from the CF-1 mouse 15-day neurotoxicity study with the L-660,599 
photodegradate be used as the basis for acute dietary risk assessment. 
For evaluation of chronic dietary risks, Merck is proposing that the 1-
year dog chronic study NOEL of 0.25 mg/kg/day be used. The dog appears 
to be the most sensitive species to long-term exposure to emamectin 
benzoate. Accordingly, chronic exposure is compared against a RfD of 
0.0025 mg/kg/day, based on the dog study results and an uncertainty 
factor of 100.

C. Aggregate Exposure

    1. Dietary exposure. Except for a temporary tolerance associated 
with an experimental use permit, no tolerances for residues of 
emamectin benzoate have been established. Merck projects that by the 
year 2,001, emamectin benzoate will be used on approximately 17% of the 
acreage for the cole, leafy non-cole vegetable, and fruiting vegetable 
crops. Chronic dietary exposure analyses were conducted for the overall 
U.S. population and 26 population subgroups. Assuming 100% of the crops 
are treated, chronic exposure for the overall U.S. population was 
estimated to be 0.000005 mg/kg BW/day, and for the most highly exposed 
subgroup, children 1 to 6 years of age, 0.000007 mg/kg BW/day.
    2. Non-dietary exposure. No products containing emamectin benzoate 
have yet been registered under the Federal Insecticide, Fungicide, and 
Rodenticide Act (FIFRA) for any food or nonfood use. No significant 
nondietary,

[[Page 45808]]

nonoccupational exposure is anticipated.
    3. Drinking water. The environmental fate of emamectin has been 
evaluated, and the compound is not expected to contaminate groundwater 
or surface water to any measurable extent.

D. Cumulative Effects

    Emamectin is a member of the avermectin family of natural and 
synthetic compounds that includes the Merck products abamectin (a 
naturally occurring compound that is the active ingredient of several 
insecticides registered under FIFRA) and ivermectin (a human and animal 
drug made from abamectin). Emamectin is made from abamectin but is less 
similar to abamectin than is ivermectin. Other companies produce 
certain other drugs that are members of the avermectin family. Some of 
the effects seen in toxicity studies of abamectin and ivermectin are 
similar to some of the effects seen in toxicity studies of emamectin. 
See the discussion of abamectin and ivermectin in 61 FR 65043 (December 
10, 1996). Merck is not aware of any information indicating what, if 
any, cumulative effect would result from exposure to two or more of 
these compounds.

E. Safety Determination

    1. U.S. population-- i. Chronic risk. Chronic exposures were 
analyzed with reference to the chronic effects RfD NOEL of 0.0025 mg/
kg/day. Assuming 100% of the crops are treated, the chronic exposure 
estimate was 0.2% of the RfD for the overall U.S. population, and 0.3% 
of the RfD for the most highly exposed subgroup, children 1 to 6 years 
of age. If 25% crop treatment is assumed, exposure estimates were less 
than 0.1% of the RfD for all population groups.
    ii. Acute risk. Acute exposure analyses were conducted for the 
overall U.S. population, and the population subgroups (1) women 13 
years and older, (2) infants, and (3) children. In addition, Tier 2 and 
Tier 3 acute analyses were conducted assessing acute exposures against 
the 0.075 mg/kg/day NOEL. These analyses showed that the margins of 
exposure (MOEs) calculated from the proposed uses of emamectin benzoate 
are acceptable whether using a highly conservative approach (Tier 2) or 
a more realistic (Tier 3) methodology. In the Tier 2 analysis, MOEs 
were well over 1,000 up to the 95th percentile of exposure for all 
population groups. In the Tier 3 analysis and assuming 100% of the 
crops are treated, MOEs up to the 99.5th percentile of exposure were 
greater than 1,000. Assuming 25% of the crop treated, MOEs were greater 
than 1,000 up to the 99.9th percentile of exposure. Results of both the 
chronic and acute dietary exposure analyses clearly demonstrate a 
reasonable certainty that no harm will result from the proposed uses of 
emamectin benzoate.
    2. Infants and children. It is Merck's position that the 
administration of emamectin benzoate has not been shown to cause 
developmental or reproductive effects at dose levels below those that 
are maternally toxic. Even if it were decided to use the 0.6 mg/kg NOEL 
from the rat developmental neurotoxicity study as an endpoint from 
which to calculate an RfD, the resulting RfD would not yield a 
different regulatory outcome unless a very high additional uncertainty 
factor were also employed. Use of such an extra uncertainty factor is 
not justified for several reasons. Emamectin benzoate is not a 
teratogen. In developmental toxicity testing, the compound caused no 
developmental effects in rabbits; in rats, it caused no malformations, 
and caused skeletal effects typical of developmental delay only at 
severely maternally toxic doses. Likewise, no reproductive toxicity or 
toxicity to pups was seen in the 2-generation reproductive toxicity 
study except at parentally toxic doses. In the developmental 
neurotoxicity study, tremors, hind-leg splay, and behavioral effects 
were seen in pups at a dose level (3.6/2.5 mg/kg/day) at which no 
maternal clinical signs were noted. However, the dams in the study were 
discarded after the lactation period without gross necropsy or 
microscopic examination. In studies in which rats dosed at similar 
levels were examined microscopically, effects (central and peripheral 
neural lesions) were seen.
    The clinical signs of avermectin-family neurotoxicity seen in 
neonatal rats are unlikely to be useful predictors of human risk. Young 
rats are considerably more sensitive to avermectin-type compounds than 
either adult rats or humans and other primates. (In neonatal rats, 
unlike humans, the P-glycoprotein levels are only a small fraction of 
the levels seen in adult rats.) Moreover, data from clinical experience 
with ivermectin, a related human drug, and studies on ivermectin and 
abamectin, a related pesticide, demonstrate that both the neonatal rat 
and the CF-1 mouse overpredict the toxicity of the avermectin-type 
compounds to humans and to non-human primates.

F. International Tolerances

    No Codex maximum residue levels (MRLs) have been established for 
residues of emamectin benzoate. (Beth Edwards)

3. Milliken & Company

PP 5E4597

    EPA has received a pesticide petition (PP 5E4597) from Milliken & 
Company, M-400, P.O Box 1927, Spartanburg, SC 29304-1927, proposing 
pursuant to section 408(d) of the Federal Food, Drug and Cosmetic Act, 
21 U.S.C. 346a(d), to amend 40 CFR 180.1001(c) to establish an 
exemption from the requirement of a tolerance for Poly(ethylene glycol) 
modified FD&C Blue No. 1, Methyl-Poly(ethylene glycol) modified FD&C 
Blue No. 1; Poly(ethylene glycol) modified Methyl Violet 2B; when used 
as inert ingredients at the rate not to exceed 0.6 parts per billion 
(ppb) to impart color to pesticidally-treated seeds. EPA has determined 
that the petition contains data or information regarding the elements 
set forth in section 408(d)(2) of the FFDCA; 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.

A. Residue Chemistry

    1. Plant metabolism. No specific residue studies have been 
conducted on the colorants in raw agricultural commodities or in 
processed foods. However, the aggregate exposure estimates, discussed 
above, are based on the assumption that an exaggerative level of PEG-
modified FD&C Blue No. 1, Methyl-PEG-modified FD&C Blue No. 1, and PEG-
modified Methyl Violet 2B applied to seeds will be absorbed by growing 
plants and enter the diet. Even based on this exaggerative assumption, 
the maximum potential dietary exposure to the colorants is minuscule.
    2. Analytical method. Section 408(c)(3)(B) provides for 
circumstances where no need exists for a practical method for detecting 
and measuring levels of pesticide residue in or on food. In this 
instance, because the colorants of interest are inert ingredients and 
since the exemption from the requirement of a tolerance has no 
numerical limitation, analytical methods are not required for 
enforcement purposes for these colorants.

B. Toxicological Profile

    1. Acute toxicity. The results of acute oral toxicity studies 
indicate that PEG-modified FD&C Blue No. 1 has very low

[[Page 45809]]

toxicity by the oral route. Specifically, PEG-modified FD&C Blue No. 1 
has an acute oral LD50 of greater than 5,000 milligrams per 
kilogram in rats. An additional test material having slightly smaller 
side chain lengths than PEG-modified FD&C Blue No. 1 also showed an 
acute oral LD50 of greater than 5,000 milligrams per 
kilogram in rats. PEG-modified FD&C Blue No. 1 is closely related to 
FD&C Blue No. 1; however, the PEG-modified FD&C Blue No. 1 is of a 
higher molecular weight than FD&C No. 1. FD&C Blue No. 1, itself, is 
exempt from the requirement of a tolerance under 40 CFR 180.1001 and 
also is cleared by the Food and Drug Administration for use in coloring 
food and for coloring drugs under 21 CFR 74.101 and 74.1101, 
respectively. The acute oral LD50 for FD&C Blue No. 1 has 
been determined to be greater than 2,000 mg/kg in rats (Lu and 
Lavallee, 1964). Thus, the acute toxicity data submitted in support of 
this petition support the conclusion that PEG-modified FD&C Blue No. 1 
is of a lower order of toxicity than FD&C Blue No. 1, itself. Such a 
result could be expected since, in general, compounds of higher 
molecular weights are more poorly absorbed and consequently are 
typically less toxic than closely related lower molecular weight 
materials.
    Along the same lines, it should be noted that Methyl-PEG-modified 
FD&C Blue No. 1, is another material that is closely related to FD&C 
Blue No. 1, but is of a higher molecular weight. Similarly, PEG-
modified Methyl Violet 2B is closely related to Methyl Violet 2B, but 
is of a higher molecular weight. Methyl Violet 2B, itself, currently is 
exempted from the requirement of a tolerance under 40 CFR 180.1001.
    Additional acute toxicity studies on the polymeric colorants of 
interest include skin and eye irritation studies. Primary dermal 
irritation studies in rabbits on PEG-modified FD&C Blue No. 1 show 
``minimally irritating'' results and primary eye irritation studies in 
rabbits show ``practically non-irritating'' results. The dermal 
sensitization studies on PEG-modified FD&C Blue No. 1 show that this 
material is not a skin sensitizer. In addition, primary dermal 
irritation studies on the test material having slightly shorter side 
chain lengths than PEG-modified FD&C Blue No. 1, show no effects. 
Finally, primary dermal irritation studies in rabbits on PEG-modified 
Methyl Violet 2B show barely perceptible erythema on abraded sites 
only, and primary eye irritation studies in rabbits show ``non-
irritating'' results.
    2. Genotoxicity. In Vitro Transformation Studies and Mouse Lymphoma 
Forward Mutation Studies on PEG-modified FD&C Blue No. 1 both show that 
this test material is inactive. Furthermore, an Ames study on Methyl-
PEG-modified FD&C Blue No. 1 shows non-mutagenic results. Mutagenicity 
studies have not been conducted on Methyl Violet 2B, PEG Analog.
    3. Reproductive and developmental toxicity. In Vitro Transformation 
Studies and Mouse Lymphoma Forward Mutation Studies on PEG-modified 
FD&C Blue No. 1 both show that this test material is inactive. 
Furthermore, an Ames study on Methyl-PEG-modified FD&C Blue No. 1 shows 
non-mutagenic results. Mutagenicity studies have not been conducted on 
Methyl Violet 2B, PEG Analog.
    4. Chronic toxicity. Chronic toxicity studies have not been 
conducted on the three colorants of interest; however, studies have 
been conducted on FD&C Blue No. 1, which is closely related to the FD&C 
Blue No. 1 PEG and methyl PEG analogs. For this substance, a chronic 
dietary No-Observed-Adverse-Effect Level (NOAEL) in mice has been shown 
to be 7,354 milligrams per kilogram body weight per day for males, and 
8,966 milligrams per kilogram per day for females. A chronic dietary 
NOAEL for rats has been shown to be 1,072 for milligrams per kilogram 
body weight per day for males and 631 milligrams per kilogram body 
weight per day for females, showing a low order of chronic toxicity.

C. Aggregate Exposure

    1. Dietary exposure. Dietary exposure to the polymeric colorants, 
if at all, will be at de minimis levels. The colorants are intended to 
be used as inert ingredients in pesticides that will be applied to 
seeds. (The purpose of the colorants is to signal users that the seeds 
have been treated with a pesticide that is not the subject of a 
tolerance or an exemption from tolerance.) Because the colorants are 
polymeric, they are not expected to be taken up by the growing plants. 
Indeed, a determination of the octanol/water partition coefficient for 
a test material identical to PEG-modified FD&C Blue No. 1, but with 
slightly longer side chain lengths, resulted in low values that 
demonstrate that the colorant would have little or no tendency to 
concentrate in the fatty portions of animals or in plants. Even 
assuming, however, that the polymeric colorants are taken up by growing 
plants, the potential dietary exposure to these materials is less than 
0.6 parts per billion (ppb) of the diet. This estimate is based on data 
presented in Knott's Handbook for Vegetable Growers, O. Lorenz and D. 
Maynard (c1988), which provides data with respect to the ``Approximate 
Number of Seeds per Ounce and per Gram and Seeding Rates for 
Traditional Plant Densities,'' and ``Yields of Vegetable Crops.''
    Although the calculated dietary exposure to the colorants is 
minuscule, it is important to note that even this extremely low 
calculated exposure clearly is a gross overestimate, given the 
polymeric nature of the colorants. Furthermore, although an acceptable 
daily intake (ADI) for the colorants of interest has not been 
established, the Joint FAO/WHO Expert Committee on Food Additives 
(JECFA) has established an ADI for FD&C Blue No. 1 of 5 mg/kg body 
weight/day, or 100 ppm of the diet. Furthermore, JECFA has established 
an ADI for PEG of 10 mg/kg/person/day, or 200 ppm of the diet. (See 
``World Health Organization Technical Report Series'', Nos. 557 and 
648.) The estimated dietary exposure to the colorants of interest is 
over two orders of magnitude below these ADIs for related compounds.
    Currently, there are no established tolerances or exemptions from 
tolerance for any of the colorants. However, the colorants are simply 
polyethylene glycol-modified versions of dyes that currently are exempt 
from the requirement of a tolerance (i.e., FD&C Blue No. 1 and Methyl 
Violet 2B).
    2. Drinking water. There is no available information regarding 
exposure to PEG-modified FD&C Blue No. 1, Methyl-PEG-modified FD&C Blue 
No. 1, or PEG-modified Methyl Violet 2B via drinking water. However, 
aerobic soil metabolism studies on PEG-modified FD&C Blue No. 1 and 
PEG-modified Methyl Violet 2B demonstrate that these colorants are 
``inherently biodegradable.'' Furthermore, the results of aerobic soil 
metabolism studies on all three colorants show that between 19% and 25% 
of each colorant degrades within 42 days. Based on these results and 
the low use levels of the colorants, significant exposure to these 
colorants in drinking water is not anticipated. Furthermore, there is 
no established Maximum Concentration Level for the polymeric colorants 
in drinking water.
    3. Non-dietary exposure. The proposed use of PEG-modified FD&C Blue 
No. 1, Methyl-PEG-modified FD&C Blue No. 1, and PEG-modified Methyl 
Violet 2B involves either application to turf grass seeds or 
application to seeds grown in an agricultural environment. Thus, there 
is no potential for significant non-occupational exposure of the 
colorants to the general population.

[[Page 45810]]

D. Cumulative Effects

    There is no reason to suspect that toxic effects of PEG-modified 
FD&C Blue No. 1, Methyl-PEG-modified FD&C Blue No. 1, PEG-modified 
Methyl Violet 2B would be cumulative with those of any other pesticide 
inert or active chemical, and there are no data to indicate that this 
would be the case. Thus, Milliken considers it appropriate to evaluate 
the potential risks of the colorants solely in the context of the 
aggregate exposure assessment.

E. Safety Determination

    1. U.S. population. Data from acute toxicity studies show FD&C Blue 
No. 1, PEG and Methyl PEG Analogs and PEG-modified Methyl Violet 2B to 
be of a very low order of toxicity. Furthermore, two compounds that are 
closely related to the colorants of interest, FD&C Blue No. 1 and 
Methyl Violet 2B, currently are exempt from the requirement of a 
tolerance under 40 CFR 180.1001 paragraphs (b) and (c), respectively. 
In addition, FD&C Blue No. 1 is cleared by FDA for use in coloring food 
and drugs. Use of the polymeric colorants of interest as inert 
ingredients in pesticides applied to turf grass seeds and seeds for 
edible plants such as beans, squash, and soybeans is not expected to 
result in significant dietary exposures. Furthermore, there currently 
are no other registered pesticidal uses in which these polymeric 
colorants are used.
    Because of the de minimis potential dietary exposures to the 
polymeric colorants, there are no dietary risk concerns associated with 
the intended use of the colorants, and there is a reasonable certainty 
that no harm will result from such use.
    2. Infants and children. The toxicity and exposure data in the 
petition are sufficiently complete to adequately address the potential 
for additional sensitivity to infants and children. Specifically, as 
discussed above, developmental and reproductive effects studies on PEG-
modified and Methyl-PEG-modified FD&C Blue No. 1 have shown no 
developmental/reproductive effects. Based on these data, together with 
the low potential dietary exposure to the colorants, there is a 
reasonable certainty that no harm will result to infants and children 
from aggregate exposure to PEG-modified FD&C Blue No. 1, and Methyl-
PEG-modified FD&C Blue No. 1. Furthermore, although developmental 
effects studies have not been conducted on PEG-modified Methyl Violet 
2B, the potential dietary exposure to this colorant is sufficiently low 
as to establish that there is a reasonable certainty that no harm will 
result to infants and children from aggregate exposure to PEG-modified 
Methyl Violet 2B.

F. International Tolerances

    There are no Codex maximum residue levels established for residues 
of PEG-modified FD&C Blue No. 1, Methyl-PEG-modified FD&C Blue No. 1, 
or PEG-modified Methyl Violet 2B. (Amelia Acierto)
[FR Doc. 97-23097 Filed 8-28-97; 8:45 am]
BILLING CODE 6560-50-F