[Federal Register Volume 63, Number 42 (Wednesday, March 4, 1998)]
[Notices]
[Pages 10609-10614]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-5563]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-794; FRL-5774-1]


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-794, must 
be received on or before April 3, 1998.
ADDRESSES: By mail submit written comments to: Public Information and 
Records Integrity Branch (7502C), 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. 119, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
    Comments and data may also be submitted electronically to: opp-
[email protected]. Follow 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

[[Page 10610]]

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. 119 at the Virginia 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:

------------------------------------------------------------------------
                                   Office location/                     
        Product Manager            telephone number          Address    
------------------------------------------------------------------------
Beth Edwards..................  Rm. 206, CM #2, 703-    1921 Jefferson  
                                 305-5400, e-mail:       Davis Hwy,     
                                 edwards.beth@epamail.   Arlington, VA  
                                 epa.gov.                               
Sidney Jackson................  Rm. 233, CM #2, 703-    Do.             
                                 305-7610, e-mail:                      
                                 jackson.sidney@epamai
l.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-794] (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 5.1/6.1 or ASCII file 
format. All comments and data in electronic form must be identified by 
the docket control number [PF-794] 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: February 24, 1998.

James Jones,

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. DowElanco

PP 8F4942

    EPA has received a pesticide petition (PP 8F4942) from DowElanco, 
9330 Zionsville Road, Indianapolis, IN 46254 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 the insecticide spinosad in or on the raw agricultural 
commodity cotton gin byproducts at 1.5 parts per million (ppm). Because 
of the amount of spinosad residue found in cotton gin byproducts as 
well as wet apple pomace (pending tolerance under PP 6F4761) and almond 
hulls and citrus dried pulp (pending tolerances under PP 7F4871) and 
the amount of cotton gin byproducts, almond hulls, citrus dried pulp, 
and apple pomace potentially included in livestock rations, a 
livestock, fat residue tolerance of 0.8 ppm, a milk residue tolerance 
of 0.05 ppm, and a milk fat residue tolerance of 0.7 ppm are also being 
proposed. The following meat and milk tolerances for residues of 
spinosad are presently pending under PP 6F4761 and PP 7F4871: meat at 
0.04 ppm, kidney and liver at 0.2 ppm, fat at 0.7 ppm, milk at 0.04 
ppm, and milk fat at 0.5 ppm. An adequate analytical method is 
available for enforcement purposes. 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. The metabolism of spinosad in plants (apples, 
cabbage, cotton, tomato, and turnip) and animals (goats and poultry) is 
adequately understood for the purposes of these tolerances. A 
rotational crop study showed no carryover of measurable spinosad 
related residues in representative test crops.
    2. Analytical method. There is a practical method (HPLC with UV 
detection) for detecting (0.004 ppm) and measuring (0.01 ppm) levels of 
spinosad in or on food with a limit of detection that allows monitoring 
of food with residues at or above the levels set for these tolerances. 
The method has had a successful method tryout in the EPA's 
laboratories.
    3. Magnitude of residues. Magnitude of residue studies were 
conducted for cotton gin byproducts at seven sites. Residues found in 
these studies ranged from less than the limit of quantitation of the 
analytical method to 0.9 ppm on cotton gin byproducts.

B. Toxicological Profile

    1. Acute toxicity. Spinosad has low acute toxicity. The rat oral 
LD50 is 3,738 mg/kg for males and >5,000 milligrams/
kilograms (mg/kg) for females, whereas the mouse oral LD50 
is >5,000 mg/kg. The rabbit dermal LD50 is >2,000 mg/kg and 
the rat inhalation LC50 is >5.18 mg/l air. In addition, 
spinosad is not a skin sensitizer in guinea pigs and does not produce 
significant dermal or ocular irritation in rabbits. End use 
formulations of spinosad that are water based suspension concentrates 
have similar low acute toxicity profiles.
    2. Genotoxicity. Short term assays for genotoxicity consisting of a 
bacterial reverse mutation assay (Ames test), an

[[Page 10611]]

in vitro assay for cytogenetic damage using the Chinese hamster ovary 
cells, an in vitro mammalian gene mutation assay using mouse lymphoma 
cells, an in vitro assay for DNA damage and repair in rat hepatocytes, 
and an in vivo cytogenetic assay in the mouse bone marrow (micronucleus 
test) have been conducted with spinosad. These studies show a lack of 
genotoxicity.
    3. Reproductive and developmental toxicity. Spinosad caused 
decreased body weights in maternal rats given 200 milligrams/kilograms/
day (mg/kg/day) by gavage (highest dose tested). This was not 
accompanied by either embryo toxicity, fetal toxicity, or 
teratogenicity. The NOELs for maternal and fetal effects in rats were 
50 and 200 mg/kg/day, respectively. A teratology study in rabbits 
showed that spinosad caused decreased body weight gain and a few 
abortions in maternal rabbits given 50 mg/kg/day (highest dose tested). 
Maternal toxicity was not accompanied by either embryo toxicity, fetal 
toxicity, or teratogenicity. The NOELs for maternal and fetal effects 
in rabbits were 10 and 50 mg/kg/day, respectively. The NOEL found for 
maternal and pup effects in a rat reproduction study was 10 mg/kg/day. 
Neonatal effects at 100 mg/kg/day (highest dose tested in the rat 
reproduction study) were attributed to maternal toxicity.
    4. Subchronic toxicity. Spinosad was evaluated in 13-week dietary 
studies and showed NOELs of 4.9 mg/kg/day in dogs, 6 mg/kg/day in mice, 
and 8.6 mg/kg/day in rats. No dermal irritation or systemic toxicity 
occurred in a 21-day repeated dose dermal toxicity study in rabbits 
given 1,000 mg/kg/day.
    5. Chronic toxicity. Based on chronic testing with spinosad in the 
dog and the rat, the EPA has set a reference dose (RfD) of 0.0268 mg/
kg/day for spinosad. The RfD has incorporated a 100-fold safety factor 
to the NOELs found in the chronic dog study. The NOELs shown in the dog 
chronic study were 2.68 and 2.72 mg/kg/day, respectively for male and 
female dogs. The NOELs shown in the rat chronic study were 2.4 and 3.0 
mg/kg/day, respectively for male and female rats. Using the Guidelines 
for Carcinogen Risk Assessment published September 24, 1986 (51 FR 
33992), it is proposed that spinosad be classified as Group E for 
carcinogenicity (no evidence of carcinogenicity) based on the results 
of carcinogenicity studies in two species. There was no evidence of 
carcinogenicity in an 18-month mouse feeding study and a 24-month rat 
feeding study at all dosages tested. The NOELs shown in the mouse 
oncogenicity study were 11.4 and 13.8 mg/kg/day, respectively for male 
and female mice. The NOELs shown in the rat chronic/oncogenicity study 
were 2.4 and 3.0 mg/kg/day, respectively for male and female rats. A 
maximum tolerated dose was achieved at the top dosage level tested in 
both of these studies based on excessive mortality. Thus, the doses 
tested are adequate for identifying a cancer risk. Accordingly, a 
cancer risk assessment is not needed.
    6. Animal metabolism. There were no major differences in the 
bioavailability, routes or rates of excretion, or metabolism of 
spinosyn A and spinosyn D following oral administration in rats. Urine 
and fecal excretions were almost completed in 48-hours post-dosing. In 
addition, the routes and rates of excretion were not affected by 
repeated administration.
    7. Metabolite toxicology. The residue of concern for tolerance 
setting purposes is the parent material (spinosyn A and spinosyn D). 
Thus, there is no need to address metabolite toxicity.
    8. Neurotoxicity. Spinosad did not cause neurotoxicity in rats in 
acute, subchronic, or chronic toxicity studies.
    9. Endocrine effects. There is no evidence to suggest that spinosad 
has an effect on any endocrine system.

C. Aggregate Exposure

    1. Dietary exposure. For purposes of assessing the potential 
dietary exposure from use of spinosad on cotton gin byproducts as well 
as from other existing or pending uses, a conservative estimate of 
aggregate exposure is determined by basing the TMRC on the proposed 
tolerance levels for spinosad and assuming that 100% of the cotton gin 
byproducts and other existing and pending crop uses grown in the U.S. 
were treated with spinosad. The TMRC is obtained by multiplying the 
tolerance residue levels by the consumption data which estimates the 
amount of crops and related foodstuffs consumed by various population 
subgroups. The use of a tolerance level and 100% of crop treated 
clearly results in an overestimate of human exposure and a safety 
determination for the use of spinosad on crops cited in this summary 
that is based on a conservative exposure assessment.
    2. Drinking water. Another potential source of dietary exposure are 
residues in drinking water. Based on the available environmental 
studies conducted with spinosad wherein it's properties show little or 
no mobility in soil, there is no anticipated exposure to residues of 
spinosad in drinking water. In addition, there is no established 
Maximum Concentration Level for residues of spinosad in drinking water.
    3. Non-dietary exposure. Spinosad is currently registered for use 
on cotton with several crop registrations pending all of which involve 
applications of spinosad in the agriculture environment. Spinosad is 
also currently registered for use on turf and ornamentals at low rates 
of application (0.04 to 0.54 lb a.i. per acre). Thus, the potential for 
non-dietary exposure to the general population is not expected to be 
significant.

D. Cumulative Effects

    The potential for cumulative effects of spinosad and other 
substances that have a common mechanism of toxicity is also considered. 
In terms of insect control, spinosad causes excitation of the insect 
nervous system, leading to involuntary muscle contractions, prostration 
with tremors, and finally paralysis. These effects are consistent with 
the activation of nicotinic acetylcholine receptors by a mechanism that 
is clearly novel and unique among known insecticidal compounds. 
Spinosad also has effects on the GABA receptor function that may 
contribute further to its insecticidal activity. Based on results found 
in tests with various mammalian species, spinosad appears to have a 
mechanism of toxicity like that of many amphiphilic cationic compounds. 
There is no reliable information to indicate that toxic effects 
produced by spinosad would be cumulative with those of any other 
pesticide chemical. Thus it is appropriate to consider only the 
potential risks of spinosad in an aggregate exposure assessment.

E. Safety Determination

    1. U.S. population. Using the conservative exposure assumptions and 
the proposed RfD described above, the aggregate exposure to spinosad 
use on cotton gin byproducts and other existing or pending crop uses 
will utilize 20.6% of the RfD for the U.S. population. A more realistic 
estimate of dietary exposure and risk relative to a chronic toxicity 
endpoint is obtained if average (anticipated) residue values from field 
trials are used. Inserting the average residue values in place of 
tolerance residue levels produces a more realistic, but still 
conservative risk assessment. Based on average or anticipated residues 
in a dietary risk analysis, the use of spinosad on cotton gin 
byproducts and other existing or pending crop uses will utilize 4.5% of 
the RfD for the U.S. population. EPA generally has no concern for 
exposures below 100% of the RfD because the RfD represents the level at 
or below which daily aggregate dietary exposure over a lifetime will 
not pose appreciable risks to human health.

[[Page 10612]]

 Thus, it is clear that there is reasonable certainty that no harm will 
result from aggregate exposure to spinosad residues on cotton gin 
products and other existing or pending crop uses.
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of spinosad, data from 
developmental toxicity studies in rats and rabbits and a 2-generation 
reproduction study in the rat are considered. The developmental 
toxicity studies are designed to evaluate adverse effects on the 
developing organism resulting from pesticide exposure during prenatal 
development. Reproduction studies provide information relating to 
effects from exposure to the pesticide on the reproductive capability 
and potential systemic toxicity of mating animals and on various 
parameters associated with the well-being of pups.
    Section 408 of the FFDCA provides that EPA may apply an additional 
safety factor for infants and children in the case of threshold effects 
to account for pre- and post-natal toxicity and the completeness of the 
database. Based on the current toxicological data requirements, the 
database for spinosad relative to pre- and post-natal effects for 
children is complete. Further, for spinosad, the NOELs in the dog 
chronic feeding study which was used to calculate the RfD (0.0268 mg/
kg/day) are already lower than the NOELs from the developmental studies 
in rats and rabbits by a factor of more than 10-fold.
    Concerning the reproduction study in rats, the pup effects shown at 
the highest dose tested were attributed to maternal toxicity. 
Therefore, it is concluded that an additional uncertainty factor is not 
needed and that the RfD at 0.0268 mg/kg/day is appropriate for 
assessing risk to infants and children.
    Using the conservative exposure assumptions previously described 
(tolerance level residues), the percent RfD utilized by the aggregate 
exposure to residues of spinosad on cotton gin byproducts and other 
existing or pending crop uses is 38.1% for children 1 to 6 years old, 
the most sensitive population subgroup. If average or anticipated 
residues are used in the dietary risk analysis, the use of spinosad on 
these crops will utilize 11.1% of the RfD for children 1 to 6 years 
old. Thus, based on the completeness and reliability of the toxicity 
data and the conservative exposure assessment, it is concluded that 
there is a reasonable certainty that no harm will result to infants and 
children from aggregate exposure to spinosad residues on cotton gin 
byproducts and other existing or pending crop uses.

F. International Tolerances

    There are no Codex maximum residue levels established for residues 
of spinosad on cotton gin byproducts or any other food or feed crop.   
(Beth Edwards)

2. Interregional Research Project

PP 4E4420 and 6E4638

    EPA has received pesticide petitions (PP 4E4420 and 6E4638) from 
the Interregional Research Project Number 4 (IR-4), 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 
combined residues (free and bound) of the herbicide metolachlor and its 
metabolites, CGA- 37913 and CGA- 49751, expressed as the parent 
compound, in or on the raw agricultural commodities (RACs) peppers at 
0.5 ppm, forage of the grass forage, fodder and hay group (excluding 
Bermudagrass), forage at 12 ppm and hay of the grass forage, fodder and 
hay group (excluding Bermudagrass) at 0.3 ppm. Time-limited tolerances 
are being proposed for peppers and grass grown for seed to allow time 
to developed magnitude of residue data from an additional three field 
trials for bell pepper and five additional field trials for grass 
forage and hay. EPA has determined that the petitions contain 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 support granting of the 
petitions. Additional data may be needed before EPA rules on the 
petitions. This notice contains a summary of the petitions submitted by 
Novartis Crop Protection, Inc. (Novartis), the registrant.

A. Residue Chemistry

    1. Plant and animal metabolism. The qualitative nature of the 
metabolism of metolachlor in plants and animals is well understood. 
Metabolism in plants involves conjugation of the chloroacetyl side 
chain with glutathione, with subsequent conversion to the cysteine and 
thiolactic acid conjugates. Oxidation to the corresponding sulfoxide 
derivatives occurs and cleavage of the side chain ether group, followed 
by conjugation with glucose. In animals, metolachlor is rapidly 
metabolized and almost totally eliminated in the excreta of rats, 
goats, and poultry. Metabolism in plants and animals proceeds through 
common Phase 1 intermediates and glutathione conjugation.
    2. Analytical method. IR-4 has submitted a practical analytical 
method involving extraction by acid reflux, filtration, partition and 
cleanup with analysis by gas chromatography using nitrogen specific 
detection. The methodology accounts for residues of CGA-37913 and CGA-
49751 which are formed from metolachlor and its metabolites under acid 
hydrolysis. The limit of quantitation (LOQ) for the method is 0.03 ppm 
for CGA-37913 and 0.05 ppm for CGA-49751. Residues of CGA-37913 and 
CGA-49751 are reported as metolachlor equivalents.
    3. Magnitude of residues. For peppers - This petition for the 
establishment of a 0.5 ppm tolerance for metolachlor on peppers is 
supported by the individual tolerances already established in a number 
of pepper varieties: bell (0.1 ppm), chili (0.5 ppm), Cubanelle (0.1 
ppm), and tabasco (0.5 ppm).
    In four field trials, 1.5 to 3.5 lbs. metolachlor per acre, was 
applied 48 hours after transplanting of bell peppers. Residues from 
these samples were less than 0.1 ppm. Metolachlor was also applied at 
2.0 to 4.0 lbs active per acre to Cubanelle peppers shortly after 
transplanting. Residues recovered from these samples were also below 
the 0.1 ppm level. In tabasco peppers, 4 lbs metolachlor per acre was 
applied as a directed spray to the pepper plants and peppers were 
harvested either 7 or 14 days after treatment. Residues of nearly 0.5 
ppm were recovered 7 days after treatment, however, the residue levels 
dropped to approximately 0.25 ppm when harvested 14 days after 
treatment. For chili peppers, metolachlor was applied post-emergence as 
a foliar application at 2.0 lbs active per acre. Samples harvested at 
approximately 40 days after treatment had residues of 0.36 ppm (as CGA-
49751), however, samples taken later than this date had residues below 
0.03 ppm. In one additional chili pepper trial, metolachlor was applied 
at rates of 1 to 4 lbs active ingredient per acre to direct seeded 
peppers. No residues were recovered from the peppers harvested 204 days 
after the application. The proposed label would allow one surface 
broadcast application of metolachlor at 1.25 to 2.0 pints (1.25 to 2.0 
lbs. active) per acre within 48 hours after transplanting peppers and 
with a pre-harvest interval of 63 days.
    For Grass Grown for Seed - This petition is supported by six field 
residue tests conducted on grasses grown for seed. Quantitative 
measurements of the metolachlor hydrolysates, CGA-37913 and CGA-49751, 
were made for all

[[Page 10613]]

samples and reported as metolachlor equivalents. In all residue tests, 
metolachlor (Dual 8E) was applied post-emergence at a maximum 
of 2.0 lbs. a.i./A at the early regrowth stage prior to weed emergence. 
The maximum residue in forage was 27 ppm (60-day PHI). Residues in 
forage declined with increasing PHI. Maximum residues in straw, 
screenings, and seed were 0.11 ppm, 0.04 ppm, and <0.08 ppm, 
respectively.

B. Toxicological Profile

    1. Acute toxicity. Metolachlor has a low order of acute toxicity. 
The combined rat oral lethal dose (LD)50 is 2,877 
milligrams(mg)/kilogram(kg). The acute rabbit dermal LD50 is 
>2,000 mg/kg and the rat inhalation lethal concentration 
(LC)50 is >4.33 mg/liter (L). Metolachlor was not irritating 
to the skin and eye. It was shown to be positive in guinea pigs for 
skin sensitization. End use formulations of metolachlor also have a low 
order of acute toxicity and cause slight skin and eye irritation.
    2. Genotoxicity. Assays for genotoxicity were comprised of tests 
evaluating metolachlor's potential to induce point mutations 
(Salmonella assay and an L5178/TK+/- mouse lymphoma assay), chromosome 
aberrations (mouse micronucleus and a dominant lethal assay) and the 
ability to induce either unscheduled or scheduled deoxyribonucleic acid 
(DNA) synthesis in rat hepatocytes or DNA damage or repair in human 
fibroblasts. The results indicate that metolachlor is not mutagenic or 
clastogenic and does not provoke unscheduled DNA synthesis.
    3. Reproductive and developmental toxicity. Adverse developmental 
and reproductive potential of metolachlor was investigated in rats and 
rabbits. The results indicate that metolachlor is not embyrotoxic or 
reproductive toxic in either species at maternally toxic doses. The no-
observed-effect level (NOEL) for developmental toxicity for metolachlor 
was 360 mg/kg/day for both the rat and rabbit while the NOEL for 
maternal toxicity was established at 120 mg/kg/day in the rabbit and 
360 mg/kg/day in the rat.
    A 2-generation reproduction study was conducted with metolachlor in 
rats at feeding levels of 0, 30, 300 and 1,000 ppm. The reproductive 
NOEL of 300 ppm (equivalent to 23.5 to 26 mg/kg/day) was based upon 
reduced pup weights in the F1a and F2a litters at the 1,000 ppm dose 
level (equivalent to 75.8 to 85.7 mg/kg/day). The NOEL for parental 
toxicity was equal to or greater than the 1,000 ppm dose level.
    4. Subchronic toxicity. Metolachlor was evaluated in a 21-day 
dermal toxicity study in the rabbit and a 6-month dietary study in 
dogs; NOELs of 100 mg/kg/day and 7.5 mg/kg/day were established in the 
rabbit and dog, respectively. The liver was identified as the main 
target organ.
    5. Chronic toxicity. A 1-year dog study was conducted at dose 
levels of 0, 3.3, 9.7, or 32.7 mg/kg/day. The Agency-determined 
reference dose(RfD) for metolachlor is based on the one year dog study 
with a NOEL of 9.7 mg/kg/day. The RfD for metolachlor is established at 
0.1 mg/kg/day using a 100-fold uncertainty factor. A combined chronic 
toxicity/carcinogenicity study was also conducted in rats at dose 
levels of 0. 1.5, 15 or 150 mg/kg/day. The NOEL for systemic toxicity 
was 15 mg/kg/day.
    6. Carcinogenicity. An evaluation of the carcinogenic potential of 
metolachlor was made from two sets of carcinogenicity studies conducted 
with metolachlor in rats and mice. EPA has classified metolachlor as a 
Group C (possible human) carcinogen and uses a Margin of Exposure (MOE) 
approach to quantify risk. This classification is based upon the 
marginal tumor response observed in livers of female rats treated with 
a high (cytotoxic) dose of metolachlor (3,000 ppm). The two studies 
conducted in mice were negative for carcinogenicity.
    A NOEL of 15 mg/kg/day from the 2 year rat feeding study was 
determined to be appropriate for use in the MOE carcinogenic risk 
assessment. However, because the chronic reference dose is lower (9.7 
mg/kg/day) than the carcinogenic NOEL (15 mg/kg/day), the EPA is using 
the Reference Dose for quantification of human risk.
    7. Estrogenic potential/endocrine disruption. Metolachlor does not 
belong to a class of chemicals known or suspected of having adverse 
effects on the endocrine system. There is no evidence that metolachlor 
has any effect on endocrine function in developmental or reproduction 
studies. Furthermore, histological investigation of endocrine organs in 
the chronic dog, rat and mouse studies conducted with metolachlor did 
not indicate that the endocrine system is targeted by metolachlor, even 
at maximally tolerated doses administered for a lifetime. Although 
residues of metolachlor have been found in raw agricultural 
commodities, there is no evidence that metolachlor bioaccumulates in 
the environment.

C. Aggregate Exposure

    1. Dietary (food) exposure. For purposes of assessing the potential 
dietary exposure to metolachlor, aggregate exposure has been estimated 
based on the Theoretical Maximum Residue Contribution (TMRC) from the 
use of metolachlor in or on raw agricultural commodities for which 
tolerances have been previously established (40 CFR 180.368). The 
incremental effect on dietary risk resulting from the addition of 
peppers to the label was assessed by assuming that exposure would occur 
at the proposed tolerance level of 0.5 ppm with 100% of the crop 
treated. The potential human dietary exposure from grasses grown for 
seed comes from the consumption of grass forage and hay by animals. 
Based on the tolerances proposed in forage (12 ppm) and hay (0.3 ppm), 
it has been determined that tolerances previously established for 
metolachlor in animal commodities of milk and meat, fat, kidney, liver 
and meat byproducts are adequate to cover secondary residues resulting 
from animal consumption of grass forage and hay.
    The TMRC is obtained by multiplying the tolerance level residue for 
all these raw agricultural commodities by the consumption data which 
estimates the amount of these products consumed by various population 
subgroups. Some of these raw agricultural commodities (e.g. corn forage 
and fodder, peanut hay) are fed to animals; thus exposure of humans to 
residues in these fed commodities might result if such residues are 
transferred to meat, milk, poultry, or eggs. Therefore, tolerances of 
0.02 ppm for milk, meat and eggs and 0.2 ppm for kidney and 0.05 ppm 
for liver have been established for metolachlor.
    In conducting this exposure assessment, it has been conservatively 
assumed that 100% of all raw agricultural commodities for which 
tolerances have been established for metolachlor will contain 
metolachlor residues and those residues would be at the level of the 
tolerance--which results in an overestimation of human exposure.
    2. Drinking water. Another potential source of exposure of the 
general population to residues of pesticides are residues in drinking 
water. Based on the available studies used by EPA to assess 
environmental exposure, Novartis anticipates that exposure to residues 
of metolachlor in drinking water will not exceed 20% of the RfD (0.02 
mg/kg/day), a value upon which the Health Advisory Level of 70 parts 
per billion (ppb) for metolachlor is based. In fact, based on 
experience with metolachlor,

[[Page 10614]]

it is believed that metolachlor will be infrequently found in 
groundwater (less than 5% of the samples analyzed), and when found, it 
will be in the low ppb range.
    3. Non-dietary exposure. Although metolachlor may be used on turf 
and ornamentals in a residential setting, that use represents less than 
0.1 percent of the total herbicide market for residential turf and 
landscape uses. Currently, there are no acceptable, reliable exposure 
data available to assess any potential risks from non-dietary exposure. 
However, given the small amount of material that is used, Novartis 
believes that the potential for non-occupational exposure to the 
general population is unlikely.

D. Cumulative Effects

    The potential for cumulative effects of metolachlor and other 
substances that have a common mechanism of toxicity has also been 
considered. Novartis believes that consideration of a common mechanism 
of toxicity with other registered pesticides in this chemical class 
(chloroacetamides) is not appropriate. EPA concluded that the 
carcinogenic potential of metolachlor is not the same as other 
registered chloroacetamide herbicides, based on differences in rodent 
metabolism (EPA Peer Review of metolachlor, 1994). Novartis maintains 
that only metolachlor should be considered in an aggregate exposure 
assessment.

E. Safety Determination

    1. U.S. population. Using the exposure assumptions described above, 
based on the completeness and reliability of the toxicity data, 
Novartis has concluded that aggregate exposure to metolachlor including 
the proposed new uses on peppers and grasses grown for seed will 
utilize approximately 3.0% of the RfD for the U.S. population. EPA 
generally has no concern for exposures below 100% of the RfD because 
the RfD represents the level at or below which daily aggregate dietary 
exposure over a lifetime will not pose appreciable risks to human 
health. Therefore, Novartis believes that there is a reasonable 
certainty that no harm will result from aggregate exposure to 
metolachlor or metolachlor residues.
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of metolachlor, data 
from developmental toxicity studies in the rat and rabbit and a 2-
generation reproduction study in the rat have been considered. The 
developmental toxicity studies are designed to evaluate adverse effects 
on the developing organism resulting from chemical exposure during 
prenatal development to one or both parents. Reproduction studies 
provide information relating to effects from exposure to a chemical on 
the reproductive capability of mating animals and data on systemic 
toxicity.
    Developmental toxicity (reduced mean fetal body weight, reduced 
number of implantations/dam with resulting decreased litter size, and a 
slight increase in resorptions/dam with a resulting increase in post-
implantation loss) were observed in studies on metolachlor in rats and 
rabbits. The NOEL's for developmental effects in both rats and rabbits 
were established at 360 mg/kg/day. The developmental effect observed in 
the metolachlor rat study is believed to be a secondary effect 
resulting from maternal stress (lacrimation, salivation, decreased body 
weight gain and food consumption and death) observed at the limit dose 
of 1,000 mg/kg/day.
    A 2-generation reproduction study was conducted with metolachlor at 
feeding levels of 0, 30, 300 and 1,000 ppm. The reproductive NOEL of 
300 ppm (equivalent to 23.5 to 26 mg/kg/day) was based upon reduced pup 
weights in the F1a and F2a litters at the 1,000 ppm dose level 
(equivalent to 75.8 to 85.7 mg/kg/day). The NOEL for parental toxicity 
was equal to or greater than the 1,000 ppm dose level.
    Section 408 of the FFDCA provides that EPA may apply an additional 
safety factor for infants and children in the case of threshold effects 
to account for pre- and post-natal toxicity and the completeness of the 
database. Based on the current toxicological data requirements, the 
database relative to pre- and post-natal effects for children is 
complete. Further, for the chemical metolachlor, the NOEL of 9.7 mg/kg/
day from the metolachlor chronic dog study, which was used to calculate 
the RfD (discussed above), is already lower than the developmental 
NOEL's of 360 mg/kg/day from the metolachlor developmental toxicity 
studies in rats and rabbits. In the metolachlor reproduction study, the 
lack of severity of the pup effects observed (decreased body weight) at 
the systemic lowest-observed-effect level (LOEL) (equivalent to 75.8 to 
85.7 mg/kg/day) and the fact that the effects were observed at a dose 
that is nearly 10 times greater than the NOEL in the chronic dog study 
(9.7 mg/kg/day) suggest there is no additional sensitivity for infants 
and children. Therefore, Novartis concludes that an additional 
uncertainty factor is not warranted to protect the health of infants 
and children and that the RfD at 0.1 mg/kg/day based on the chronic dog 
study is appropriate for assessing aggregate risk to infants and 
children from use of metolachlor.
    Using the exposure assumptions described above, Novartis concludes 
that the approximate percentages of the RfD that will be utilized by 
aggregate exposure to residues of metolachlor including published and 
pending tolerances is 1% for U. S. population, for nursing infants less 
than 1%, 3% for non-nursing infants, 3% for children 1 to 6 years old 
and 2% for children 7 to 12 years old.
    Therefore, based on the completeness and reliability of the 
toxicity data and the conservative exposure assessment, Novartis 
concludes that there is a reasonable certainty that no harm will result 
to infants and children from aggregate exposure to metolachlor 
residues.

F. International Tolerances

    There are no Codex Alimentarius Commission (CODEX) maximum residue 
levels (MRL's) established for residues of metolachlor in or on raw 
agricultural commodities.   (Sidney Jackson)

[FR Doc. 98-5563 Filed 3-3-98:45 am]
BILLING CODE 6560-50-F