[Federal Register Volume 63, Number 18 (Wednesday, January 28, 1998)]
[Notices]
[Pages 4252-4259]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-2088]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-787; FRL-5763-6]


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-787, must 
be received on or before February 27, 1998.
ADDRESSES: By mail submit written comments to: Public Information and 
Records Integrity Branch, Information Resources and Services Division 
(7502C), 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 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 record. Information not marked confidential 
may be disclosed publicly by EPA without prior notice. All written 
comments will be available for public

[[Page 4253]]

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:

------------------------------------------------------------------------
                                   Office location/                     
        Product Manager            telephone number          Address    
------------------------------------------------------------------------
Amelia M. Acierto.............  Rm. 4W60, 4th. floor,   2800 Crystal    
                                 CSI #2, 703-308-8377,   Drive,         
                                 e-                      Arlington, VA  
                                 mail:acierto.amelia@e
pamail.epa.gov.                        
Adam Heyward..................  Rm. 206, CM #2, 703-    1921 Jefferson  
                                 305-5518, e-mail:       Davis Hwy.,    
                                 heyward.                Arlington, VA  
                                 [email protected].                  
Joseph Tavano.................  Rm. 214, CM #2, 703-    Do.             
                                 305-6411, e-mail:                      
                                 tavano.joseph@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-787] (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-787] and appropriate petition 
number. Electronic comments on notice may be filed online at many 
Federal Depository Libraries.

List of Subjects

    Environmental protection, Agricultural commodities, Feed additives, 
Food additives, Pesticides and pests, Reporting and recordkeeping 
requirements.

    Dated:January 20, 1998

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. Gowan Company

PP 6F4738

     In May, 1996, EPA received a pesticide petition (PP 6F4738) from 
Gowan Company, P. O. Box 5569, Yuma, AZ 85366-5569. The petition 
proposed, pursuant to section 408 of the Federal Food, Drug, and 
Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 to 
establish tolerances for the acaricide hexythiazox and its metabolites 
in or on the raw agricultural commodities stone fruits (except plums) 
at 1 part per million (ppm), almonds at 0.2 ppm and almond hulls at 10 
ppm, and also in milk, cattle meat and cattle fat at 0.05 ppm, and 
cattle meat byproducts at 0.1 ppm (April 30, 1997, 62 FR 23455-23457) 
(FRL-5600-8). In April 1997, the registrant amended the tolerance 
petition by proposing to establish a tolerance for stone fruits 
including plums at 1 ppm, a tolerance for prunes at 5 ppm, and a 
tolerance for all tree nuts at 0.2 ppm. The proposed tolerances for 
animal products were unchanged. 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 
support granting of the petition. Additional data may be needed before 
EPA rules on the petition. The proposed analytical method is high 
performance liquid chromatography with an ultraviolet detector. As 
required by section 408(d) of the FFDCA, as recently amended by the 
Food Quality Protection Act (FQPA) Pub. L. 104-170, Gowan Company 
included in the petition a summary of the petition and authorization 
for the summary to be published in the Federal Register in a notice of 
receipt of the petition.

A. Residue Chemistry

    1. Plant metabolism. The metabolism of hexythiazox in apples, 
citrus, grapes and pears has been studied. The major portion of the 
residue is parent compound. The metabolites are hydroxycyclohexyl and 
ketocyclohexyl analogs of hexythiazox and the amide formed by loss of 
the cyclohexyl ring.
    2. Analytical method. An adequate analytical method (HPLC with UV 
detection) is available for enforcement purposes. Parent compound and 
all of its metabolites are converted to a common moiety before 
analysis.
    3. Magnitude of residues. Twenty-four stone fruit residue trials 
were conducted over 3-years. The geographic distribution of the trials 
agrees with the recommendation given in the ``EPA Residue Chemistry 
Guidance''(1994). In these trials, the maximum combined residues of 
hexythiazox and its metabolites were 0.52 ppm. Twelve tree nut residue 
trials were conducted over 4 years. In these trials, the maximum 
combined residues of hexythiazox and its metabolites were 0.17 ppm in 
almond nutmeat and 7.5 ppm in the raw agricultural commodity almond 
hulls.

B. Toxicological Profile

    1. Acute toxicity. The acute oral and dermal LD50 of 
technical hexythiazox is greater than 5,000 milligram/kilograms (mg/
kg), and the 4-hour acute inhalation LC50 is greater than 2 
mg/L. It is not a dermal irritant or sensitizer and is a mild eye 
irritant.
    2. Genotoxicity. The following genotoxicity tests were all 
negative:

[[Page 4254]]

 Ames gene mutation, CHO gene mutation, CHO chromosome aberration, 
mouse micronucleus and rat hepatocyte unscheduled DNA synthesis.
    3. Reproductive and developmental toxicity. Hexythiazox has not 
been observed to induce developmental or reproductive effects. The 
lowest reproductive or developmental no-observed-effect-level (NOEL) 
observed was 200 milligram/kilograms/day (mg/kg/day), the highest dose 
tested, in a 2-generation rat reproduction study.
    4. Subchronic toxicity. The Office of Pesticide Programs has 
established the RfD for hexythiazox at 0.025 mg/kg/day. The RfD for 
hexythiazox is based on a 1-year dog feeding study with a NOEL of 2.5 
mg/kg/day and an uncertainty factor of 100. The endpoint effect of 
concern was hypertrophy of the adrenal cortex in both sexes, decreased 
red blood cell counts, hemoglobin content and hematocrit in males.
    5. Chronic toxicity. The Agency has classified hexythiazox as a 
category C (possible human) carcinogen based on an increased incidence 
of hepatocellular carcinomas (p = 0.028) and combined adenomas/
carcinomas (p = 0.024) in female mice at the highest dose tested (1,500 
ppm) when compared to the controls as well as a significantly increased 
(p >0.001) incidence of pre-neoplastic hepatic nodules in both males 
and females at the highest dose tested. The decision supporting a 
category C classification was based primarily on the fact that only one 
species was affected and mutagenicity studies were negative. In 
classifying hexythiazox as a category C carcinogen, the Agency 
concluded that a quantitative estimate of the carcinogenic potential 
for humans should be calculated because of the increased incidence of 
liver tumors in the female mouse. A Q1* of 0.039 (mg/kg/
day)-1 in human equivalents was calculated.

C. Aggregate Exposure

    Tolerances have been established (40 CFR 180.448) for the combined 
residues of hexythiazox [trans-5-(4-chlorophenyl)-N-cyclohexyl-4-
methyl-2-oxothiazolidine-3-carboxamide] and its metabolites containing 
the (4-chlorophenyl)-4-methyl-2-oxo-3-thiazolidine moiety in or on 
apples at 0.02 ppm and pears at 0.3 ppm. The nature and metabolism of 
hexythiazox in plants and animals is adequately understood.
    Hexythiazox is also registered for use on outdoor ornamental plants 
by commercial applicators only. It is believed that non-occupational 
exposure from this use is very low. Hexythiazox is not registered for 
greenhouse, lawn, garden, or residential use. The environmental fate of 
hexythiazox has been evaluated, and the compound is not expected to 
contaminate groundwater or surface water to any measurable extent.
    1. Dietary exposure. The Agency has calculated in the Federal 
Register of February 21, 1996 (61 FR 6152-6154) (FRL-5350-6), that 
current uses on apples and pears would result in an exposure of 
0.000051 mg/kg/day for the U.S. population, assuming that all residues 
are at tolerance levels and 100% of the crops are treated. Non-nursing 
infants, the subgroup having the highest exposure, would have an 
exposure of 0.000600 mg/kg/day. Using the same conservative 
assumptions, it is calculated that the current and proposed uses 
together would result in an exposure of 0.001133 mg/kg for the U.S. 
population and 0.007256 mg/kg/day for non-nursing infants, which 
remains the most highly exposed subgroup.
    Actual exposure will be much lower, however. Only a small fraction 
of these crops will be treated with hexythiazox, and average residues 
are far below the tolerance levels. For example, residues in apples 
treated at 10 times the currently approved application rate remained 
below the limit of quantitation, 0.01 ppm. Also, residues in apple 
juice are expected to be less than 50% of the residue level in the 
whole fruit. Average residues in stone fruits except cherries are 
expected to be 7% of the proposed tolerance level, average residues in 
cherries are expected to be 11% of the tolerance level and average 
residues in almond nutmeat are expected to be below 20% of the proposed 
tolerance level. Furthermore, only a very small percentage of crops 
(less than 1% up to 5%, depending on the crop) are expected to be 
treated with hexythiazox. When actual residues rather than tolerance 
levels and the percentage of treated crop are taken into account, then 
the actual exposure is estimated to be 0.0000069 mg/kg/day for the U.S. 
population.
    2. Drinking water. The Agency has not conducted a detailed analysis 
of potential exposure to hexythiazox via drinking water or outdoor 
ornamental plants. However, it is believed that chronic exposure from 
these sources is very small.
    3. Non-dietary exposure. No developmental, reproductive or 
mutagenic effects have been observed with hexythiazox. Therefore, an 
analysis of acute exposure has not been conducted.

D. Cumulative Effects

    At this time the Agency has not reviewed available information 
concerning the potentially cumulative effects of hexythiazox and other 
substances that may have a common mechanism of toxicity. For purposes 
of this petition only, the Agency is considering only the potential 
risks of hexythiazox in its aggregate exposure.

E. Determination of Safety for U.S. Population

    1. Chronic risk. The Agency has calculated (FR 61 6152-6154), 
assuming that residues are at tolerance levels and 100% of crops are 
treated, that the current use on apples and pears utilizes 0.2% of the 
reference dose (RfD) for the U.S. population and 2.4% of the RfD for 
non-nursing infants. Using these same assumptions, it is calculated 
that all current and proposed uses would result in TMRCs equivalent to 
4.5% of the RfD for the U.S. population and 29.0% of the RfD for non-
nursing infants. However, when actual residues rather than tolerance 
levels and the percent of crop treated are taken into account, actual 
chronic risk for the U.S. population is expected to be only 0.43% of 
the RfD.
    The actual dietary carcinogenic risk to the U.S. population is 
calculated to be 2.7  x  10-7, which is below the Agency's 
criterion of 1  x  10-6.
    2. Acute risk. An estimate of acute risk with this compound has not 
been conducted since no acute reproductive or developmental effects 
have been observed.

F. Determination of Safety for Infants and Children

    In assessing the potential for additional sensitivity of infants 
and children to residues of hexythiazox, EPA considered data from 
developmental toxicity studies in the rat and rabbit and a 2-generation 
study in the rat. The developmental toxicity studies are designed to 
evaluate adverse effects on the developing organism resulting from 
pesticide exposure during pre-natal development to one or both parents. 
Reproduction studies provide information relating to effects from 
exposure to the pesticide on the reproductive capability of mating 
animals and data on systemic toxicity.
    No developmental or reproductive effects have been observed in any 
study with hexythiazox. The lowest acute NOEL was 2,400 ppm in the diet 
(200 mg/kg/day), the highest dose tested, in the 2-generation rat 
reproduction study. In the rat developmental study, the maternal and 
fetotoxic NOEL was 240 mg/kg/day and the developmental

[[Page 4255]]

NOEL was 2,160 mg/kg/day, the highest dose tested. In the rabbit 
developmental study, the maternal and developmental NOEL was 1,080 mg/
kg/day, the highest dose tested.
    Taking into account current toxicological data requirements, the 
database for hexythiazox relative to pre-natal and post-natal effects 
is complete. In the rat developmental study, the NOELs for maternal 
toxicity and fetotoxicity were the same, which suggests that there is 
no special pre-natal sensitivity in the absence of maternal toxicity. 
Furthermore, the lowest developmental or reproductive NOEL is two 
orders of magnitude higher than the chronic NOEL on which the RfD is 
based. It is concluded that there is a reasonable certainty of no harm 
to infants and children from aggregate exposure to hexythiazox 
residues.

G. International Tolerances

    Codex maximum residue levels (MRLs) of 1 mg/kg (1 ppm) have been 
established for residues of hexythiazox in cherries and peaches. The 
U.S. tolerance proposal for stone fruits is in harmony with these MRLs. 
There are no Codex MRLs for the other commodities in this petition. 
There are no Canadian or Mexican MRLs for hexythiazox. (Adam Heyward)

2. Monsanto Company

PP 5E4503

    EPA has received a pesticide petition (PP 5E4503) from Monsanto 
Company, 700 14th St., NW., Washington, DC 20005, 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 a tolerance 
for residues of the inert ingredient 4-(dichloroacetyl)-1-oxa-4-
azospiro [4.5] decane (MON 4660) in or on the raw agricultural 
commodity, corn, resulting from early post-emergence applications. The 
analytical method, which determines the residue by gas-liquid 
chromatography using an electron-capture detector has been reviewed by 
the Agency and accepted 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.

A. Residue Chemistry

    1. Plant metabolism. The metabolism of MON 4660 in corn was studied 
with radiolabeled MON 4660 in the greenhouse and the field. Parent MON 
4660 was not found in any of the corn samples. MON 4660 is rapidly and 
extensively metabolized to a large number of highly polar metabolites 
characterized as weak organic acids or residues conjugated to natural 
sugars.
    2. Analytical method. Monsanto has developed an analytical method 
using gas liquid chromatography with electron capture detection that 
has a verified limit of quantitation of 0.005 ppm for parent MON 4660 
in all corn matrices. This method has been validated by the Agency.
    3. Magnitude of residues. Monsanto has conducted 14 residue field 
studies with MON 4660 applied pre-emergence to corn. Analysis of corn 
forage, silage, fodder and grain showed no residues above the limit of 
quantitiation of 0.005 ppm. Two residue field studies with MON 4660 
applied pre-emergence to corn at rates 20 and 28 times the proposed 
maximum use rate showed no measurable residues (<0.005 ppm) in corn 
grain. Based on these results it was concluded that the potential for 
measurable concentration of MON 4660 in processed commodities of corn 
was very low. Eight residue field trials (2 samples per trial) were 
conducted with MON 4660 applied early post-emergence with corn plants 6 
to 11 inches tall. Analysis of corn forage, fodder and grain again 
showed no measurable residues (<0.005 ppm). These residues, derived 
from postemergence applications are below the established Sensitivity 
of Method Tolerance for corn (0.005 ppm).

B. Toxicological Profile

    The toxicology data considered in support of the revised tolerance 
include the following:
    1. Acute toxicity-- i. An acute oral toxicity study in the rat with 
an LD50 of 2,600 mg/kg. Toxicity Category III.
    ii. An acute dermal toxicity study in the rabbit with an 
LD50 of > 5,000 mg/kg. Toxicity Category IV.
    iii. An acute inhalation study in the rat with a 4-hour inhalation 
LC50 of 0.27 mg/L. Toxicity Category III.
    iv. A rabbit eye irritation study in which 4-(dichloroacetyl)-1-
oxa-4-azospiro [4.5] decane is determined not to be an eye irritant. 
Toxicity Category III.
    v. A dermal irritation study which exhibited slight skin 
irritation. Toxicity Category IV.
    vi. A guinea pig dermal sensitization study in which 4-
(dichloroacetyl)-1-oxa-4-azospiro [4.5] decane is determined to be a 
skin sensitizer.
    2. Genotoxicity. Mutagenicity studies including Salmonella 
typhimurium/mammalian plate incorporation (Ames) assay, CHO/HGPRT gene 
mutation assay, DNA repair studies (rat hepatocytes), and Salmonella/
mammalian activation gene mutation (Ames) assay were negative with and 
without activation.
    3. Reproductive and developmental toxicity-- i. A rat developmental 
effects study with a NOEL for maternal toxicity of 10 mg/kg/day and 
developmental toxicity of 75 mg/kg/day.
    ii. A rabbit developmental effects study with a NOEL for maternal 
toxicity of 10 mg/kg/day and developmental toxicity of 30 mg/kg/day.
    iii. A 2-generation reproduction study in the rat fed diet levels 
of 0, 10, 100, and 1,000 ppm. There were no treatment-related effects 
on mating, fertility or offspring survival in this study. The NOEL for 
toxicity in parental animals and offspring was 100 ppm (6 to 7 mg/kg/
day). As there were no adverse effects on reproductive performance, the 
NOEL for reproductive toxicity was 1,000 ppm (57 to 72 mg/kg/day).
    4. Subchronic toxicity-- i. A 90-day oral toxicity study in the rat 
with a NOEL of 120 parts per million (ppm) or 12 mg/kg/day.
    ii. A 90-day oral (gavage) study in the dog with a NOEL of 30 mg/
kg/day, the highest dose tested.
    5. Chronic toxicity-- i. A mouse oncogenicity study in which 5 
groups of 60 male and 60 female CD-1 mice were administered diets 
containing 4-(dichloroacetyl)-1-oxa-4-azospiro [4.5] decane at 
concentrations 0, 5, 80, 800 or 2,500 ppm for approximately 18 months. 
These concentrations corresponded to 0, 0.7, 10.7, 108 and 350 mg/kg/
day in males and 0, 1, 16.8, 167 and 556 mg/kg/day in females. The 
primary target organs were liver, lung and stomach. The NOEL for both 
oncogenic and non-oncogenic effects was considered to be 10.7 mg/kg/day 
in males and 116.8 mg/kg/day in females.
    ii. A chronic toxicity/oncogenicity study in rats in which 5 groups 
of 60 male and 60 female rats were administered diets containing 4-
(dichloroacetyl)-1-oxa-4-azospiro [4.5] decane for approximately 23 
months. Target concentrations were 0, 5, 50, 500, or 1,600 ppm for 
males and, 0, 5, 50, or 1,200 ppm for females. These concentrations 
correspond to 0, 0.2, 2.2, 22 and 71 mg/kg/day in males and 0, 0.3, 
2.8, 29 and 69 mg/kg/day in females. The primary effects in this study 
occurred in the liver and stomach. The NOEL for oncogenic effects is 22 
mg/kg/day in males and 29 mg/kg/day in females. The NOEL for non-

[[Page 4256]]

 oncogenic effects is 2.2 mg/kg/day in males and 2.8 mg/kg/day in 
females.
    6. Animal metabolism. Because field trial residue data showed non-
detectable residues of MON 4660 in corn, neither animal metabolism nor 
residue transfer studies with livestock were required. It is considered 
likely that metabolism will be similar to that of other 
dichloroacetamide safeners in mammals which are characterized by 
extensive metabolism and elimination of most of the residue from the 
body with very low levels of parent safener, if any, retained in the 
tissues. The major route of metabolism is typically glutathione 
conjugation followed by formation of an aldehyde intermediate which is 
then either oxidized to an oxamic acid or reduced to the corresponding 
alcohol.
    7. Metabolite toxicology. The metabolism of MON 4660 is extensive 
and results in a large number of polar metabolites each of which is 
present in soil or corn plants in very low concentrations. These 
metabolites have not been identified as being of toxic concern.
    Based on the available toxicity data, Monsanto believes the RfD for 
MON 4660 will be 0.02 mg/kg/day based on a 2-year feeding study in rats 
with a NOEL of 2.2 mg/kg/day and application of an uncertainty factor 
of 100. For cancer risk assessment for MON 4660, Monsanto believes that 
margin of exposure assessment should be calculated using the 
carcinogenic NOEL of 10.7 mg/kg/day observed in the mouse, which was 
the most sensitive species.

C. Aggregate Exposure

    1. Dietary exposure-- i. Food. Monsanto has used the Theoretical 
Maximum Residue Contribution as a conservative estimate of the 
potential dietary exposure for MON 4660. This approach assumes that 
100% of all raw agricultural commodities for which tolerances have been 
established for acetochlor, bear tolerance-level (0.005 ppm) residues 
of MON 4660. This over-estimate of actual dietary exposure provides a 
quite conservative basis for risk assessment.
    ii. Drinking water. Although MON 4660 is stable to hydrolyis and 
shows only a small amount of photodegradation in soil and in water, it 
is rapidly degraded in the soil. The aerobic soil half-life is 
approximately 18 days. This low persistence in the environment combined 
with the low application rate (maximum of 0.4 pound per acre) indicates 
that MON 4660 is not likely to be present in groundwater. Based on 
these considerations, Monsanto does not anticipate exposure to residues 
of MON 4660 in drinking water. The EPA has not established a Maximum 
Concentration Level or a health advisory level for residues of MON 4660 
in drinking water.
    2. Non-dietary exposure. MON 4660 is used only as a safener or 
antidote to the effects of acetochlor herbicide on corn seed or 
seedlings. It is sold only as part of acetochlor herbicide end-use 
products which are classified as Restricted Use by EPA which means they 
are used only by certified applicators and are not available to the 
general public. Herbicide products containing MON 4660 are not 
registered for residential, home owner, or other non-crop uses. They 
are thus not used in parks, school grounds, public buildings, roadsides 
or rights-of-way or other public areas. Commercial cornfields are 
generally located well away from public areas where incidental contact 
could occur. Therefore, the general public is very unlikely to have any 
non-dietary exposure to MON 4660.

D. Cumulative Effects

    Monsanto has no reliable data or information to suggest that MON 
4660 has toxic effects that arise from toxic mechanisms that are common 
to other substances. Therefore, a consideration of common toxic 
mechanism and cumulative effects with other substances is not 
appropriate for MON 4660, and Monsanto is considering only the 
potential effects of MON 4660 in this exposure assessment.

E. Safety Determination

    1. U.S. population-- i. Chronic risk. The conservative estimate of 
aggregate chronic exposure is 2.0 x 10-6 mg/kg/day. This 
potential exposure represents only 0.01% of the RfD of 0.02 mg/kg/day 
and provides a Margin of Exposure of 5,350,000 when compared to the 
10.7 mg/kg/day carcinogenic reference point. EPA generally has no 
concern for exposures below 100% of the RfD and there are adequate 
margins of safety for cancer. Monsanto concludes there is a reasonable 
certainty of no harm resulting from exposure to MON 4660.
    ii. Acute risk. The acute toxicity of MON 4660 is low, and there 
are no concerns for acute dietary, occupational or non-occupational 
exposures to MON 4660.
    2. Infants and children. Employing the same conservative TMRC 
estimates of exposure used in the risk assessment for the general 
population, Monsanto has calculated that the aggregate exposures for 
nursing infants, non-nursing infants, children age 1-6 and children age 
7-12 are less than one-tenth of 1% of the RfD for each group.
    Monsanto notes the developmental toxicity NOELs for rats (75 mg/kg/
day) and rabbits (30 mg/kg/day) are 34-fold and 14-fold higher than the 
NOEL of 2.2 mg/kg/day in the chronic rat study on which the RfD is 
based. This indicates that the RfD is adequate for assessing risk to 
children. Also, the developmental toxicity NOELs for rats and rabbits 
are higher than the NOELs for maternal toxicity (10 mg/kg/day in each 
specie) indicating that the offspring were no more sensitive to MON 
4660 than were the parents.
    In the 2-generation reproduction study in rats, the NOEL for pup 
toxicity (57-72 mg/kg/day) was higher than the NOEL for parental or 
systemic effects (6-7 mg/kg/day) indicating that offspring were no more 
sensitive to MON 4660 than were the parents. Also, the NOEL for pup 
toxicity (57-72 mg/kg/day) was 25 to 33-fold higher than the NOEL for 
chronic toxicity upon which the RfD is based.
    Monsanto believes that these data do not indicate an increased pre-
natal or post-natal sensitivity of children and infants to MON 4660 
exposure and concludes that the 100-fold uncertainty factor used in the 
RfD is adequate to protect infants and children.

F. International Tolerances

    The Codex Alimentarius Commission has not established a maximum 
residue level for MON 4660. (Amelia Acierto)

3. Rohm and Haas Company

PP 5F4587

    EPA has received a pesticide petition (PP 5F4587) from Rohm and 
Haas Company, 100 Independence Mall West, Philadelphia, PA 19106-2399, 
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 a tolerance for residues of Tebufenozide, benzoic 
acid,3,5-dimethyl-,1-(1,1-dimethylethyl)-2-(4-ethylbenzoyl) hydrazide 
in or on the raw agricultural commodity pecans at .05 parts per million 
(ppm). 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 tebufenozide in plants 
(apples, beets,

[[Page 4257]]

grapes, rice and sugar) is adequately understood for the purposes of 
these tolerances. The metabolism of tebufenozide in all crops was 
similar and involves oxidation of the alkyl substituents of the 
aromatic rings primarily at the benzylic positions. The extent of 
metabolism and degree of oxidation are a function of time from 
application to harvest. In all crops, parent compound comprised the 
majority of the total dosage. None of the metabolites were in excess of 
10% of the total dosage. The metabolism of tebufenozide in goats and 
hens proceeds along the same metabolic pathway as observed in plants. 
No accumulation of residues in tissues, milk or eggs occurred.
    2. Analytical method. High performance liquid chromatographic 
(HPLC) analytical method using ultraviolet (UV) or mass selective 
detection has been developed for pecans. The method involves Soxhlet 
extraction with solvents, purification of the extracts by liquid-liquid 
partitions and final purification of the residues using solid phase 
extraction column chromatography. The limit of quantitation of the 
method is 0.01 ppm (HPLC) analytical method using (UV) or mass 
selective detection has been developed for pecans. The method involves 
Soxhlet extraction with solvents, purification of the extracts by 
liquid-liquid partitions and final purification of the residues using 
solid phase extraction column chromatography. The limit of quantitation 
of the method is 0.01 ppm.

B. Toxicological Profile

    1. Acute toxicity. Tebufenozide has low acute toxicity. 
Tebufenozide Technical was practically non-toxic by ingestion of a 
single oral dose in rats and mice (LD50 > 5,000 mg/kg) and 
was practically non-toxic by dermal application (LD50 > 
5,000 mg/kg). Tebufenozide Technical was not significantly toxic to 
rats after a 4-hr inhalation exposure with an LC50 value of 
4.5 mg/L (highest attainable concentration), is not considered to be a 
primary eye irritant or a skin irritant and is not a dermal sensitizer. 
An acute neurotoxicity study in rats did not produce any neurotoxic or 
neuropathologic effects.
    2. Genotoxicity. Tebufenozide technical was negative (non-
mutagenic) in an Ames assay with and without hepatic enzyme activation 
and in a reverse mutation assay with E. coli. Tebufenozide technical 
was negative in a hypoxanthine guanine phophoribosyl transferase 
(HGPRT) gene mutation assay using Chinese hamster ovary (CHO) cells in 
culture when tested with and without hepatic enzyme activation. In 
isolated rat hepatocytes, tebufenozide technical did not induce 
unscheduled DNA synthesis (UDS) or repair when tested up to the maximum 
soluble concentration in culture medium. Tebufenozide did not produce 
chromosome effects in vivo using rat bone marrow cells or in vitro 
using Chinese hamster ovary cells (CHO). On the basis of the results 
from this battery of tests, it is concluded that tebufenozide is not 
mutagenic or genotoxic.
    3. Reproductive and developmental toxicity-- i. No Observable 
Effect Levels (NOELs) for developmental and maternal toxicity to 
tebufenozide were established at 1,000 mg/kg/day (Highest Dose Tested) 
in both the rat and rabbit. No signs of developmental toxicity were 
exhibited.
    ii. In a 2-generation reproduction study in the rat, the 
reproductive/developmental toxicity NOEL of 12.1 mg/kg/day was 14-fold 
higher than the parental (systemic) toxicity NOEL 10 ppm 0.85 mg/kg/
day. Equivocal reproductive effects were observed only at the 2,000 ppm 
dose.
    iii. In a second rat reproduction study, the equivocal reproductive 
effects were not observed at 2,000 ppm (the NOEL equal to 149-195 mg/
kg/day) and the NOEL for systemic toxicity was determined to be 25 ppm 
(1.9-2.3 mg/kg/day).
    4. Subchronic toxicity-- i. The NOEL in a 90-day rat feeding study 
was 200 ppm (13 mg/kg/day for males, 16 mg/kg/day for females). The 
Lowest Observed Effect Level (LOEL) was 2,000 ppm (133 mg/kg/day for 
males, 155 mg/kg/day for females). Decreased body weights in males and 
females was observed at the LOEL of 2,000 ppm. As part of this study, 
the potential for tebufenozide to produce subchronic neurotoxicity was 
investigated. Tebufenozide did not produce neurotoxic or 
neuropathologic effects when administered in the diets of rats for 3 
months at concentrations up to and including the limit dose of 20,000 
ppm (NOEL = 1,330 mg/kg/day for males, 1,650 mg/kg/day for females).
    ii. In a 90-day feeding study with mice, the NOEL was 20 ppm (3.4 
and 4.0 mg/kg/day for males and females, respectively). The LOEL was 
200 ppm (35.3 and 44.7 mg/kg/day for males and females, respectively). 
Decreases in body weight gain were noted in male mice at the LOEL of 
200 ppm.
    iii. A 90-day dog feeding study gave a NOEL of 50 ppm (2.1 mg/kg/
day for males and females). The LOEL was 500 ppm (20.1 and 21.4 mg/kg/
day for males and females, respectively). At the LOEL, females 
exhibited a decrease in rate of weight gain and males presented an 
increased reticulocyte.
    iv. A 10-week study was conducted in the dog to examine the 
reversibility of the effects on hematological parameters that were 
observed in other dietary studies with the dog. Tebufenozide was 
administered for 6 weeks in the diet to 4 male dogs at concentrations 
of either 0 or 1,500 ppm. After the 6th week, the dogs receiving 
treated feed were switched to the control diet for 4 weeks. 
Hematological parameters were measured in both groups prior to 
treatment, at the end of the 6-week treatment, after 2-weeks of 
recovery on the control diet and after 4-weeks of recovery on the 
control diet. All hematological parameters in the treated/recovery 
group were returned to control levels indicating that the effects of 
tebufenozide on the hemopoietic system are reversible in the dog.
    v. In a 28-day dermal toxicity study in the rat, the NOEL was 1,000 
mg/kg/day, the highest dose tested. Tebufenozide did not produce 
toxicity in the rat when administered dermally for 4-weeks at doses up 
to and including the limit dose of 1,000 mg/kg/day.
    5. Chronic toxicity-- i. A 1-year feeding study in dogs resulted in 
decreased red blood cells, hematocrit, and hemoglobin and increased 
Heinz bodies, reticulocytes, and platelets at the LOEL of 8.7 mg/kg/
day. The NOEL in this study was 1.8 mg/kg/day.
    ii. An 18-month mouse carcinogenicity study showed no signs of 
carcinogenicity at dosage levels up to and including 1,000 ppm, the 
highest dose tested.
    iii. In a combined rat chronic/oncogenicity study, the NOEL for 
chronic toxicity was 100 ppm (4.8 and 6.1 mg/kg/day for males and 
females, respectively) and the LOEL was 1,000 ppm (48 and 61 mg/kg/day 
for males and females, respectively). No carcinogenicity was observed 
at the dosage levels up to 2,000 ppm (97 mg/kg/day and 125 mg/kg/day 
for males and females, respectively).
    6. Animal metabolism. The adsorption, distribution, excretion and 
metabolism of tebufenozide in rats was investigated. Tebufenozide is 
partially absorbed, is rapidly excreted and does not accumulate in 
tissues. Although tebufenozide is mainly excreted unchanged, a number 
of polar metabolites were identified. These metabolites are products of 
oxidation of the benzylic ethyl or methyl side chains of the molecule. 
These metabolites were detected in plant and other animal (goat, hen, 
rat) metabolism studies.

[[Page 4258]]

    7. Metabolite toxicology. Common metabolic pathways for 
tebufenozide have been identified in both plants (apple, beet, grape, 
and sugar) and animals (goat, hen, rat). The metabolic pathway common 
to both plants and animals involves oxidation of the alkyl substituents 
(ethyl and methyl groups) of the aromatic rings primarily at the 
benzylic positions. Extensive degradation and elimination of polar 
metabolites occurs in animals such that residue are unlikely to 
accumulate in humans or animals exposed to these residues through the 
diet.
    8. Endocrine disruption. The toxicology profile of tebufenozide 
shows no evidence of physiological effects characteristic of the 
disruption of the hormone estrogen. Based on structure-activity 
information, tebufenozide is unlikely to exhibit estrogenic activity. 
Tebufenozide was not active in a direct in vitro estrogen binding 
assay. No indicators of estrogenic or other endocrine effects were 
observed in mammalian chronic studies or in mammalian and avian 
reproduction studies. Ecdysone has no known effects in vertebrates. 
Overall, the weight of evidence provides no indication that 
tebufenozide has endocrine activity in vertebrates.

C. Aggregate Exposure

    1. Dietary exposure--i. Food. Tolerances for residues of 
tebufenozide are currently expressed as benzoic acid, 3,5-dimethyl-1-
(1,1-dimethylethyl)-2(4-ethylbenzoyl) hydrazide. Tolerances currently 
exist for residues on apples at 1.0 ppm (import tolerance) and on 
walnuts at 0.1 ppm (see 40 CFR 180.482). In addition to this action, a 
request to establish a tolerance for pecans, other petitions are 
pending for the following tolerances: pome fruit, livestock 
commodities, wine grapes (import tolerance), cotton, the crop subgroups 
leafy greens, leaf petioles, head and stem Brassica and leafy Brassica 
greens, and kiwifruit (import tolerance).
    ii. Acute risk. No appropriate acute dietary endpoint was 
identified by the Agency. This risk assessment is not required.
    iii. Chronic risk. For chronic dietary risk assessment, the 
tolerance values are used and the assumption that all of these crops 
which are consumed in the U.S. will contain residues at the tolerance 
level. The theoretical maximum residue contribution (TMRC) using 
existing and future potential tolerances for tebufenozide on food crops 
is obtained by multiplying the tolerance level residues (existing and 
proposed) by the consumption data which estimates the amount of those 
food products consumed by various population subgroups and assuming 
that 100% of the food crops grown in the U.S. are treated with 
tebufenozide. The Theoretical Maximum Residue Contribution (TMRC) from 
current and future tolerances is calculated using the Dietary Exposure 
Evaluation Model (Version 5.03b, licensed by Novigen Sciences Inc.) 
which uses USDA food consumption data from the 1989-1992 survey. With 
the current and proposed uses of tebufenozide, the TMRC estimate 
represents 20.1% of the RfD for the U.S. population as a whole. The 
subgroup with the greatest chronic exposure is non-nursing infants 
(less than 1 year old), for which the TMRC estimate represents 52.0% of 
the RfD. Using anticipate residue levels for these crops utilizes 3.38% 
of the RfD for the U.S. population and 12.0% for non-nursing infants. 
The chronic dietary risks from these uses do not exceed EPA's level of 
concern.
    3. Drinking water. An additional potential source of dietary 
exposure to residues of pesticides are residues in drinking water. 
Review of environmental fate data by the Environmental Fate and Effects 
Division concludes taht tebufenozide is moderately persistent to 
persistent and mobile, and could potentially leach to groundwater and 
runoff to surface water under certain environmental conditions. 
However, in terrestrial field dissipation studies, residues of 
tebufenozide and its soil metabolites showed no downward mobility and 
remained associated with the upper layers of soil. Foliar interception 
(up to 60% of the total dosage applied) by target crops reduces the 
ground level residues of tebufenozide. There is no established Maximum 
Concentration Level (MCL) for residues of tebufenozide in drinking 
water. No drinking water health advisory levels have been established 
for tebufenozide.
    There are no available data to perform a quantitative drinking 
water risk assessment for tebufenozide at this time. However, in order 
to mitigate the potential for tebufenozide to leach into groundwater or 
runoff to surface water, precautionary language has been incorporated 
into the product label. Also, to the best of our knowledge, previous 
experience with more persistent and mobile pesticides for which there 
have been available data to perform quantitative risk assessments have 
demonstrated that drinking water exposure is typically a small 
percentage of the total exposure when compared to the total dietary 
exposure. This observation holds even for pesticides detected in wells 
and drinking water at levels nearing or exceeding established MCLs. 
Considering the precautionary language on the label and based on our 
knowledge of previous experience with persistent chemicals, significant 
exposure from residues of tebufenozide in drinking water is not 
anticipated.
    4. Non-dietary exposure. Tebufenozide is not registered for either 
indoor or outdoor residential use. Non-occupational exposure to the 
general population is therefore not expected and not considered in 
aggregate exposure estimates.

D. Cumulative Effects

    The potential for cumulative effects of tebufenozide with other 
substances that have a common mechanism of toxicity was considered. 
Tebufenozide belongs to the class of insecticide chemicals known as 
diacylhydrazines. The only other diacylhydrazine currently registered 
for non-food crop uses is halofenozide. Tebufenozide and halofenozide 
both produce a mild, reversible anemia following subchronic/chronic 
exposure at high doses; however, halofenozide also exhibits other 
patterns of toxicity (liver toxicity following subchronic exposure and 
developmental/systemic toxicity following acute exposure) which 
tebufenozide does not. Given the different spectrum of toxicity 
produced by tebufenozide, there is no reliable data at the molecular/
mechanistic level which would indicate that toxic effects produced by 
tebufenozide would be cumulative with those of halofenozide (or any 
other chemical compound).
    In addition to the observed differences in mammalian toxicity, 
tebufenozide also exhibits unique toxicity against target insect pests. 
Tebufenozide is an agonist of 20-hydroxyecdysone, the insect molting 
hormone, and interferes with the normal molting process in target 
lepidopteran species by interacting with ecdysone receptors from those 
species. Unlike other ecdysone agonists such as halofenozide, 
tebufenozide does not produces symptoms which may be indicative of 
systemic toxicity in beetle larvae (Coleopteran species). Tebufenozide 
has a different spectrum of activity than other ecdysone agonists. In 
contrast to the other agonists such as halofenozide which act mainly on 
coleopteran insects, tebufenozide is highly specific for lepidopteran 
insects.
    Based on the overall pattern of toxicity produced by tebufenozide 
in mammalian and insect systems, the compound's toxicity appears to be 
distinct from that of other chemicals, including organochlorines,

[[Page 4259]]

organophosphates, carbamates, pyrethroids, benzoylureas, and other 
diacylhydrazines. Thus, there is no evidence to date to suggest that 
cumulative effects of tebufenozide and other chemicals should be 
considered.

E. Safety Determination

    1. U.S. population. Using the conservative exposure assumptions 
described above and taking into account the completeness and 
reliability of the toxicity data, the dietary exposure to tebufenozide 
from the current and future tolerances will utilize 20.1% of the RfD 
for the U.S. population and 52.0% for non-nursing infants under 1-year 
old. Using anticipate residue levels for these crops utilizes 3.38% of 
the RfD for the U.S. population and 12.0% for non-nursing infants. 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. Rohm and Haas concludes that there is a reasonable certainty 
that no harm will result from aggregate exposure to tebufenozide 
residues to the U.S. population and non-nursing infants.
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of tebufenozide, data 
from developmental toxicity studies in the rat and rabbit and two 2-
generation reproduction studies in the rat are considered. The 
developmental toxicity studies are designed to evaluate adverse effects 
on the developing organism resulting from pesticide exposure during 
pre-natal development to one or both parents. Reproduction studies 
provide information relating to effects from exposure to the pesticide 
on the reproductive capability of mating animals and data on systemic 
toxicity. Developmental toxicity was not observed in developmental 
studies using rats and rabbits. The NOEL for developmental effects in 
both rats and rabbits was 1,000 mg/kg/day, which is the limit dose for 
testing in developmental studies.
    In the 2-generation reproductive toxicity study in the rat, the 
reproductive/ developmental toxicity NOEL of 12.1 mg/kg/day was 14-fold 
higher than the parental (systemic) toxicity NOEL (0.85 mg/kg/day). The 
reproductive (pup) LOEL of 171.1 mg/kg/day was based on a slight 
increase in both generations in the number of pregnant females that 
either did not deliver or had difficulty and had to be sacrificed. In 
addition, the length of gestation increased and implantation sites 
decreased significantly in F1 dams. These effects were not replicated 
at the same dose in a second 2-generation rat reproduction study. In 
this second study, reproductive effects were not observed at 2,000 ppm 
(the NOEL equal to 149-195 mg/kg/day) and the NOEL for systemic 
toxicity was determined to be 25 ppm (1.9-2.3 mg/kg/day).
    Because these reproductive effects occurred in the presence of 
parental (systemic) toxicity and were not replicated at the same doses 
in a second study, these data do not indicate an increased pre-natal or 
post-natal sensitivity to children and infants (that infants and 
children might be more sensitive than adults) to tebufenozide exposure. 
FFDCA section 408 provides that EPA shall 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 
data base unless EPA concludes that a different margin of safety is 
appropriate. Based on current toxicological data discussed above, an 
additional uncertainty factor is not warranted and the RfD at 0.018 mg/
kg/day is appropriate for assessing aggregate risk to infants and 
children. Rohm and Haas concludes that there is a reasonable certainty 
that no harm will occur to infants and children from aggregate exposure 
to residues of tebufenozide.

F. International Tolerances

    There are no approved CODEX maximum residue levels (MRLs) 
established for residues of tebufenozide. (Joseph Tavano)

[FR Doc. 98-2088 Filed 1-27-98; 8:45 am]
BILLING CODE 6560-50-F