[Federal Register Volume 64, Number 46 (Wednesday, March 10, 1999)]
[Notices]
[Pages 11874-11879]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-5823]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-862; FRL-6063-3]


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-862, must 
be received on or before April 9, 1999. 
ADDRESSES: By mail submit written comments to: Information and Records 
Integrity Branch, Public Information and Services Divison (7502C), 
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 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. 119 at the 
address

[[Page 11875]]

given above, from 8:30 a.m. to 4 p.m., Monday through Friday, excluding 
legal holidays.

FOR FURTHER INFORMATION CONTACT: Mary L. Waller, Fungicide Branch, 
Registration Division (7505C), Office of Pesticide Programs, 
Environmental Protection Agency, 401 M St., SW, Washington, DC 20460. 
Office location, telephone number, and e-mail address: Rm. 249, Crystal 
Mall #2, 1921 Jefferson Davis Highway, Arlington, VA 22202, (703) 305-
6117; e-mail:waller. [email protected].
SUPPLEMENTARY INFORMATION: EPA has received a pesticide petition as 
follows proposing the establishment and/or amendment of regulations for 
residues of certain pesticide chemical 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 this petition 
contains 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-862] (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 file format or 
ASCII file format. All comments and data in electronic form must be 
identified by the docket control number [PF-862] 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 22, 1999.

James Jones,

Director, Registration Division, Office of Pesticide Programs.

Summary of Petition

    The petitioner summaries of the pesticide petitions are printed 
below as required by section 408(d)(3) of the FFDCA. The summary of 
each petition was prepared by the petitioner and represents the views 
of the petitioner. 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 7F4816

    EPA has received a pesticide petition (PP 7F4816) from American 
Cyanamid Company, P.O. Box 400 Princeton, NJ 08543-0400 proposing, 
pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act 
(FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing a 
tolerance for residues of dimethomorph, (E,Z)4-[3-(4-chlorophenyl)-3-
(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]morpholine in or on the raw 
agricultural commodity cereal grains (Crop Group 15) and forage of 
cereal grain crops (Crop Group 16) at 0.05 parts per million (ppm) and 
fodder and straw of cereal grain crops (Crop Group 16) at 0.10 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 dimethomorph in plants is 
adequately understood for the purposes of these tolerances. A 
rotational crop study showed the potential for indirect or inadvertent 
residues of dimethomorph in or on commodities of cereal crops.
    2. Analytical method. There is a practical method for measuring 
0.050 ppm of dimethomorph in or on commodities of cereal crops. This 
gas chromatography method with nitrogen-phosphorus detection (M3112) is 
appropriate for enforcement purposes. Confirmation of residues is 
provided by liquid chromatography/mass spectroscropy of the final 
extract of this method.
    3. Magnitude of residues. The magnitude of residue studies were 
conducted for wheat as a rotational crop to potatoes treated at 1.4 x 
the maximum labeled rate. Residues found in these studies were below 
the level of quantitation (LOQ) in the forage and grain samples from 
all six trials and in the hay, and straw samples from four of the 
trials. The maximum observed residue (sample means) was 0.057 ppm for 
hay, and 0.086 ppm for straw for the other two trials. Therefore, at 
the maximum labeled rate, residues of dimethomorph in or on hay are 
expected to be below the LOQ (< 0.05 ppm) and residues in or on straw 
are expected to be less than 0.10 ppm.

B. Toxicological Profile

    1. Acute toxicity. An acute oral toxicity study in the Sprague-
Dawley rat for dimethomorph technical with a LD50 of 4,300 
milligram per kilogram bodyweight (mg/kg bwt) for males and 3,500 mg/kg 
bwt for females. Based upon EPA toxicity criteria, the acute oral 
toxicity category for dimethomorph technical is Category III or 
slightly toxic. Oral LD50 studies were conducted on the two 
isomers (E and Z) alone: An acute oral toxicity study in the Wistar rat 
for the E-isomer with a LD50 greater than 5,000 mg/kg bwt 
for males and approximately 5,000 mg/kg bwt for females. An acute oral 
toxicity study in the Wistar rat for the Z-isomer with a 
LD50 greater than 5,000 mg/kg bwt for both males and 
females. An acute dermal toxicity study in the Wistar rat for 
dimethomorph technical with a dermal LD50 greater than 5,000 
mg/kg bwt for both males and females. Based on the EPA toxicity 
category criteria, the Acute dermal toxicity category for dimethomorph 
is Category IV or relatively non-toxic. A 4-hour inhalation study in 
Wistar rats for dimethomorph technical with a LC50 greater 
than 4.2 milligram per liter (mg/L) for both males and females. Based 
on the EPA toxicity category criteria, the acute inhalation toxicity 
category for dimethomorph technical is Category IV or relatively non-
toxic.
    2. Genotoxicty. Salmonella reverse gene mutation assays (2 studies) 
were negative up to a limit dose of 5,000 g/plate. Chinese 
hamster lung cells were negative in V79 cells up to toxic doses in 2 
studies. Two Chinese hamster lung structural chromosomal studies were

[[Page 11876]]

reportedly positive for chromosomal aberrations at the highest dose 
tested (HDT) (160 g/ml/-S9; 170 g/ml/+S9). 
Dimethomorph induced only a weak response in increasing chromosome 
aberrations in this test system. These results were not confirmed in 
two micronucleus tests under in vivo conditions. Structural Chromosomal 
Aberration studies were weakly positive, in human lymphocyte cultures, 
but only in S9 activated cultures treated at the HDT (422 g/
ml) which was strongly cytotoxic. Dimethomorph was negative in the 
absence of activation at all doses and the positive in human lymphocyte 
cultures was only in S9 activated cultures treated at the HDT (422 
g/ml) which was strongly cytotoxic. Dimethomorph was negative 
in the absence of activation at all doses and the positive clastogenic 
response observed under the in vitro conditions was not confirmed in 
two in vivo micronucleus assays. Micronucleus assay (2 studies) 
indicated that dimethomorph was negative for inducing micronuclei in 
bone marrow cells of mice following i.p. administration of doses up to 
200 mg/kg or oral doses up to the limit dose of 5,000 mg/kg. Thus, 
dimethomorph was found to be negative in these studies for causing 
cytogenic damage in vivo. Dimethomorph was negative for inducing 
unscheduled DNA synthesis in cultured rat liver cells at doses up to 
250 /ml, a weak cytotoxic level. Dimethomorph was negative for 
transformation in Syrian hamster embryo cells treated in the presence 
and absence of activation up to cytotoxic concentrations (265 
g/ml/+S9; 50 g/ml-S9).
    3. Reproductive and developmental toxicity. A rat developmental 
toxicity study with a maternal toxicity lowest-observed-adverse-effect 
Level (LOAEL) of 160 mg/kg/day and a maternal toxicity no-observed 
adverse-effect level (NOAEL) of 60 mg/kg/day. The NOAEL for 
developmental toxicity is 60 mg/kg/day. Dimethomorph is not teratogenic 
in the Sprague-Dawley rat. A rabbit development toxicity study with 
parental LOAEL for systemic toxicity of 80 mg/kg/day, and a NOAEL of 24 
mg/kg/day. The NOAEL for fertility and reproductive function was 80 mg/
kg/day, the HDT.
    4. Subchronic toxicity A 90-day dog dietary study in Sprague-Dawley 
rats with a NOAEL of greater than or equal to 73 mg/kg/day in males and 
82 mg/kg/day in females, the HDT. A 90-day dog dietary study with a 
NOAEL 15 mg/kg/day, and a LOAEL of 43 mg/kg/day.
    5. Chronic toxicity. A 2-year oncogenicity study in Sprague-Dawley 
rats with a NOAEL for systemic toxicity of 9 mg/kg/day for males and 12 
mg/kg/day for females. The LOAEL for systemic toxicity is 36 mg/kg/day 
for males and 58 mg/kg/day for females. A 1-year chronic toxicity study 
in dogs with a NOAEL of 14.7 mg/kg/day and a LOAEL of 44.6 mg/kg/day. A 
2-year oncogenicity study in Sprague-Dawley rats with a NOAEL for 
systemic toxicity of 9 mg/kg/day for males and 11 mg/kg/day for 
females. The LOAEL for system toxicity was 34 mg/kg/day for males and 
46 mg/kg/ day for females. There was no evidence of increased incidence 
of neoplastic lesions in treated animals. The NOAEL for oncogenicity is 
95 mg/kg/day for males and 132 mg/kg/day for females, the HDT. A 2-year 
oncogenicity study in mice with a NOAEL for systemic toxicity of 100 
mg/kg/day, and LOAEL of 1,000 mg/kg/day. There was no evidence of 
increased incidence of neoplastic lesions in treated animals. The NOAEL 
for oncogenicity is 1,000 mg/kg/day, the HDT.
    6. Animal metabolism. Results from livestock and rat metabolism 
studies show that orally administered dimethomorph was rapidly excreted 
by the animals. The principal route of elimination is the feces.
    7. Metabolite toxicology. There were no metabolites identified in 
plant or animal commodities which require regulation.
    8. Endocrine disruption. There is no evidence of effects of 
dimethomorph on the endocrine system. There were no changes noted in 
organ weights for the pituitary, thyroid, ovaries or testes. There was 
no increased incidence of mammary tumors observed. No effects on 
fertility or reproduction were noted and there was no evidence of 
related histopathological changes in reproductive or endocrine system 
organs.

C. Aggregate Exposure

    1. Dietary exposure. Dietary exposure should be based upon the 
Theoretical Maximum Residue Concentration (TMRC) from the established 
tolerances for residues of dimethomorph at 0.05 ppm in or on potato; 
for the proposed tolerances for residues of dimethomorph at 2.0 ppm in 
or on grapes; and 0.15 ppm on potatoes wet peel; for the proposed 
tolerances for indirect and inadvertent residues of dimethomorph at 
0.05 ppm in or on cereal grains, and in or on fodder and straw of 
cereal grain crops, and from the time-limited tolerances (i.e. at 1.0 
ppm for cantaloupes, cucumbers, squash, and watermelons) which were 
established under Section 18 emergency exempt ions and which are not 
due to expire at or near completion of this regulatory action.
    i. Food. The goat and poultry metabolism studies demonstrate that 
there is no reasonable expectation of transfer of residues to meat, 
milk, poultry, or eggs from potato, grape, and cereal crop commodities. 
Therefore, no consumption data associated with meat, milk, poultry or 
eggs should be included in the calculation of the TMRC. Except for the 
permanent tolerances on potato tubers, there are no other permanent 
U.S. tolerances for dimethomorph.
    ii. Drinking water. The predicted dimethomorph surface and ground 
water concentrations are well below the drinking water level of 
concern. Using the SCI-GROW model to generate the Estimated 
Environmental Concentration (EEC) of dimethomorph residues in ground 
water, the projected EEC is 0.26 parts per billion (ppb). Using the 
Generic Estimated Environmental Concentration (GENEEC) model to 
estimate acute and chronic EECs of dimethomorph residues in surface 
water, the projected EEC ranged from a peak of 28 ppb to a 56 day 
concentration of 24 ppb. The level of concern for chronic exposure to 
residues of dimethomorph range from 960 ppb for children 1-6 years old 
to 3,400 ppb for the U.S. population and males 13 years and older. 
Therefore, American Cyanamid believes that exposure from water is below 
the level of concern for all of the populations examined. In addition, 
American Cyanamid believes that the aggregate (food, and water) chronic 
exposure for infants, children, and adults does not exceed the level of 
concern and adverse health effects from chronic exposure to 
dimethomorph in food, and water are not expected in these populations.
    2. Non-dietary exposure. In the United States, dimethomorph is 
registered only for use on potatoes. Thus, there is no potential for 
non-dietary exposure.

D. Cumulative Effects

    There is no information to indicate that any toxic effects produced 
by dimethomorph would be cumulative with those of any other chemical. 
The fungicidal mode of action of dimethomorph is unique; dimethomorph 
inhibits cell wall formation only in Oomycete fungi. The result is 
lysis of the cell wall which kills growing cells and inhibits spore 
formation in mature hyphae. This unique mode of action and limited pest 
spectrum suggest that there is little or no potential for cumulative 
toxic effects in mammals. In addition, the toxicity studies submitted 
to support this

[[Page 11877]]

petition do not indicate that dimethomorph is a particularly toxic 
compound.

E. Safety Determination

    1. U.S. population. The established reference dose (RfD) is 0.1 mg/
kg bwt/day, based on a NOAEL of 10 mg/kg bwt/day from a 2-year dietary 
toxicity study in rats that demonstrated decreased bwt, and liver foci 
in females. The established RfD is also based on an uncertainty factor 
of 100. The TMRC from the established tolerances for residues in or on 
potato along with the current Section 18 time-limited tolerances 
(cantaloupes, watermelons, cucumbers, and squash, as well as expiring 
tolerances for tomato commodities) utilizes less than 4% of the RfD for 
all population subgroups. The TMRC for grapes and cereal grains is not 
expected to cause the RfD to be exceeded.
    2. Infants and children. American Cyanamid believes that the 
results of the studies submitted to support this package provide no 
evidence that dimethomorph caused reproductive, developmental or 
fetotoxic effects. No such effects were noted at dose levels which were 
not maternally toxic. The NOAELs observed in the developmental and 
reproductive studies were 6 to 65 times higher than the NOAEL (10 mg/kg 
bwt/day) used to establish the RfD. There is no evidence to indicate 
that children or infants would be more sensitive than adults to toxic 
effects caused by exposure to dimethomorph.

F. International Tolerances

    No Codex maximum residue levels (MRLs) have been established for 
dimethomorph to date.

2. BASF Corporation

PP 7F4880

    EPA has received a pesticide petition (7F4880) from BASF 
Corporation, 26 Davis Drive, Post Office Box 13528, Research Triangle 
Park, North Carolina 27709-3528, proposing pursuant to section 408(d) 
of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), 
to amend 40 CFR part 180 by establishing a tolerance for combined 
residues of kresoxim-methyl (methyl (E)-2-methoxyimino-2-[2-(o-
tolyloxymethyl) phenyl] acetate) and the glycoside conjugates of its 
metabolites 2-[o-(o-hydroxymethylphenoxymethyl) phenyl]-2-
(methoxyimino) acetic acid and 2-[o-(p-hydroxy-o-methylphenoxymethyl) 
phenyl]-2-(methoxyimino) acetic acid in or on the raw agricultural 
commodities pome fruit, grapes and pecans at 0.30 parts per million 
(ppm) for pome fruit, 1.0 ppm for grapes, 0.15 ppm for pecans and 0.70 
ppm for apple pomace. 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. BASF Corporation notes that metabolism in 
plants is understood.
    2. Analytical method. The proposed analytical method involves 
extraction, enzyme hydrolysis, partition, clean-up and detection of 
residues by high performance liquid chromotography using ultra-violet 
(HPLC/UV) detection.
    3. Magnitude of residues. Twelve grape residue trials were 
conducted in six States. Residues of kresoxim-methyl and its two 
metabolites were measured by HPLC/UV. The analytical method had a limit 
of detection (LOD) of 0.05 ppm for each of the three analytes. Residues 
ranged from < 0.15 ppm to 0.79 ppm.
    Nineteen apple residue trials were conducted in 12 States. Residues 
of kresoxim-methyl and its two metabolites were measured by HPLC/UV. 
The analytical method had a LOD of 0.05 ppm for each of the three 
analytes. Residue of parent and metabolites ranged from < 0.15 to 0.23 
ppm.
    Eight pear residue trials were conducted in five States. Residues 
of kresoxim-methyl and its two metabolites were measured by HPLC/UV. 
The analytical method had a LOD of 0.05 ppm for each of the three 
analytes. Residues of parent plus metabolites ranged from < 0.15 to 
0.26 ppm.
    Six pecan residue trials were conducted in five States. Residues of 
kresoxim-methyl and its two metabolites were measured by HPLC/UV. The 
analytical method had a LOD of 0.05 ppm for each of the three analytes. 
No residue of parent or metabolites was found in any sample above the 
LOD.

B. Toxicological Profile

    1. Acute toxicity--Acute/subchronic toxicology. Based on available 
acute toxicity data, kresoxim-methyl does not pose any acute toxicity 
risks. Acute toxicology studies place technical-grade kresoxim-methyl 
in Toxicity Category IV for acute oral and Category III for acute 
dermal and acute inhalation toxicity. The material is not an eye 
irritant, a primary dermal irritant or a skin sensitizer. Additionally, 
in acute and subchronic neurotoxicity studies, kresoxim-methyl did not 
show any signs of neurotoxicity at dose levels up to and including 
2,000, and 1,267 milligram/kilogram/day (mg/kg/day), respectively.
    2. Genotoxicty. With regard to the liver tumors, kresoxim-methyl is 
not a genotoxic agent and is not an initiator of the carcinogenic 
process. The increased incidence of liver tumors in rats is the result 
of liver tumor promoting properties of the test substance.
    3. Reproductive and developmental toxicity--i. Reproductive 
toxicity. The 2-generation reproduction study with rats resulted in a 
reproductive no-observed adverse effect level (NOAEL) of 1,625 mg/kg/
day, and a maternal NOAEL of 100 mg/kg/day. These NOAEL values are 
significantly higher than the NOAEL from the 2 year feeding study in 
rats used to establish the reference dose (RfD).
    ii. Developmental toxicity. The teratogenicity study in rats 
resulted in a developmental toxicity NOAEL of 1,000 mg/kg/day, and a 
maternal toxicity NOAEL of 1,000 mg/kg/day. These NOAEL values are 
significantly higher than the NOAEL from the 2 year feeding study in 
rats used to establish the RfD.
    4. Subchronic toxicity--i. Acute/subchronic toxicology. Based on 
available acute toxicity data, kresoxim-methyl does not pose any acute 
toxicity risks. Acute toxicology studies place technical-grade 
kresoxim-methyl in Toxicity Category IV for acute oral and Category III 
for acute dermal and acute inhalation toxicity. The material is not an 
eye irritant, a primary dermal irritant or a skin sensitizer. 
Additionally, in acute and subchronic neurotoxicity studies, kresoxim-
methyl did not show any signs of neurotoxicity at dose levels up to and 
including 2,000 and 1,267 mg/kg/day, respectively.
    ii. Subchronic toxicology--a. Teratology - Rat. A teratogenicity 
study in the rat with doses at 100, 400, and 1,000 mg/kg/day by gavage 
was performed with a maternal NOAEL of 1,000 mg/kg/day and fetal NOAEL 
of 1,000 mg/kg/day.
    b. Teratology - Rabbits. A teratogenicity study in the rabbit with 
doses at 100, 400, and 1,000 mg/kg/day by gavage was performed with a 
maternal NOAEL of 1,000 mg/kg/day and fetal NOAEL of 1,000 mg/kg/day.
    c. Mutagenicity. Modified Ames Test (2 studies; point mutation): 
Negative; In Vitro chinese hamster ovary hypoxanthine guanine 
phophoribosyl transferase (CHO/HGPRT) (point

[[Page 11878]]

mutation): Negative; In Vitro Cytogenetics Chromosome Damage Human 
Lymphocytes: Negative; In Vivo Chromosome Mouse Micronucleus: Negative; 
In Vitro DNA Damage & Repair Rat Hepatocytes: Negative; UDS ex Vivo DNA 
Damage & Repair Wistar Rats (Single Oral Dose): Negative; UDS ex Vivo 
DNA Damage & Repair Wistar Rats (3 Week Feeding): Negative.
    5. Chronic toxicity--i. Threshold effects. Based on review of the 
available data, BASF believes the RfD for kresoxim-methyl will be based 
on the 2 year feeding study in rats with a threshold NOAEL of 36 mg/kg/
day in males, and 47 mg/kg/day in females. Using an uncertainty factor 
of 100, the RfD is calculated to be 0.36 mg/kg/day.
    ii. Non-threshold effects - carcinogenicity. Kresoxim-methyl was 
shown to be non-carcinogenic in mice. In the rat carcinogenicity study, 
a statistically significant increase in liver tumors was observed in 
both male and female animals at 370 and 746 mg/kg/day, and 503 and 985 
mg/kg/day dose levels, respectively. Kresoxim-methyl is not a genotoxic 
agent and mechanistic studies have shown that the increased incidence 
of liver tumors in rats is the result of liver tumor promoting 
properties of the test substance. Kresoxim-methyl is not an initiator 
of the carcinogenic process. Based on the available data, the mechanism 
of promotion is the induction of liver cell proliferation of the test 
substance. The data available also indicate that dose levels which do 
not induce liver toxicity neither induce cell proliferation nor enhance 
the carcinogenic process. Therefore, a threshold for liver 
carcinogenicity in rats can be defined to be approximately 40 mg/kg/
day.
    Based on the results of the carcinogenicity study in mice, the 
results of genotoxicity testing, the results of the 24 month chronic 
feeding/oncogenicity study in rats; and auxiliary mechanistic data 
showing that kresoxim-methyl is not an initiator of the carcinogenic 
process, BASF believes that the threshold approach to regulating 
kresoxim-methyl is appropriate.

C. Toxicity Data Supporting Kresoxim-methyl Tolerances

    1. Chronic feeding--i. Nonrodent. A 12 month feeding study in the 
dog with doses of 29, 142, and 738 mg/kg/day was performed with a NOAEL 
of 138 mg/kg/day for males, and 761 mg/kg/day for females. The only 
effect observed was reduced body weights (bwt) in male dogs at the 
highest dose tested (HDT).
    ii. Chronic feeding/oncogenicity - Rats. A 24 month chronic 
feeding/oncogenicity study in the rat with doses at 9, 36, 370, and 746 
mg/kg/day for males and 12, 48, 503, and 985 mg/kg/day for females was 
performed with a NOAEL of 36 mg/kg/day in males, and 47 mg/kg/day in 
females. Reduced bwt changes were observed in male, and female rats in 
the highest two dose groups. Histopathologically, changes in the liver 
were observed in either or both of the highest two dose groups for 
male, and female rats. These changes consisted of increased liver 
weight, increased hepatocellular hypertrophy, increased incidence and 
severity of eosinophilic foci of hepatocellular alterations, and 
increased incidence and degree of severity of bile duct proliferation. 
Associated with the liver, an increase of serum-gamma-
glutamyltransferase values was observed. A statistically significant 
increase in liver tumors was observed in both male, and female animals 
at 370 mg/kg/day and 985 mg/kg/day, respectively. With regard to the 
liver tumors, kresoxim-methyl is not a genotoxic agent and is not an 
initiator of the carcinogenic process. The increased incidence of liver 
tumors in rats is the result of liver tumor promoting properties of the 
test substance. Based on the available data, the mechanism of promotion 
is the induction of liver cell proliferation of the test substance. The 
data available also indicate that dose levels which do not induce liver 
toxicity neither induce cell proliferation nor enhance the carcinogenic 
process. Therefore, a threshold for liver carcinogenicity in rats can 
be defined to be approximately 40 mg/kg/day.
    iii. Oncogenicity - Mice. A mouse oncogenicity study using dosage 
levels at 60, 304, and 1,305 mg/kg/day for males, and 81, 410, and 
1,662 mg/kg/day for females was performed with a NOAEL of 304 mg/kg/day 
for males, and 81 mg/kg/day for females, with no evidence of 
oncogenicity. Bwt changes were observed in both male, and female mice 
in the highest dose group and only in the females in the 410 mg/kg/day 
group. Histopathology was limited only to the highest dose group and 
consisted of increased incidence of renal papillary necrosis for both 
male, and female mice and increased incidence and higher degree of 
severity of liver amyloidosis in females only.
    iv. 2-Generation reproduction - Rats. A 2-generation reproductive 
study in the rat with doses at 5, 100, 407, and 1,625 mg/kg/day was 
performed with a NOAEL of 100 mg/kg/day for parental and developmental 
toxicity, and a NOAEL of 1,625 mg/kg/day for reproduction toxicity. 
Decreased body weight was seen in both the pups and parents. Reduced 
serum-gamma-glutamyltransferase was seen in F0 males and both sexes of 
the F1 generation, and reduced kidney weights were seen in the F1 
generation at the 407 and 1,625 mg/kg/day dose levels. Decreased fat 
storage was observed in F0 and F1 male livers at the 407 and 1,625 mg/
kg/day dose levels.
    6. Animal metabolism. BASF Corporation notes that metabolism in 
animals is understood.

D. Aggregate Exposure

    1. Dietary exposure. For purposes of assessing the potential 
chronic dietary exposure, BASF has estimated aggregate exposure based 
on the Theoretical Maximum Residue Contribution (TMRC) from the 
proposed tolerance for kresoxim-methyl on pome fruit at 0.30 ppm, 
grapes at 1.0 ppm, and pecans at 0.15 ppm. The TMRC is a ``worse case'' 
estimate of dietary exposure since it is assumed that 100% of all crops 
for which tolerances are established are treated and that pesticide 
residues are always found at the tolerance levels.
    i. Food. Dietary exposure to residues of kresoxim-methyl in or on 
food will be limited to residues on pome fruit, grapes, and pecans. 
Apple pomace is fed to animals; thus exposure of humans to residues in 
apple pomace might result if such residues carry through to meat, milk, 
poultry, or eggs. However, BASF has concluded that there is no 
reasonable expectation that measurable residues of kresoxim-methyl will 
occur in meat, milk, poultry, or eggs from this use. There are no other 
established U.S. tolerances for kresoxim-methyl, and there are no 
currently registered uses for kresoxim-methyl on food or feed crops in 
the U.S.
    Dietary exposure to residues of kresoxim-methyl from the proposed 
tolerances on pome fruit, grapes, and pecans would account for less 
than 0.15% of the RfD (.36 mg/kg/day) for the general population of the 
U.S. The most highly exposed group in the subpopulation groups would be 
non-nursing infants < 1 year old, which uses 0.88% of the RfD.
    ii. Drinking water. Other potential sources of exposure for the 
general population to residues of kresoxim-methyl are residues in 
drinking water and exposure from non-occupational sources. Based on the 
available studies, BASF does not anticipate exposure to residues of 
kresoxim-methyl in drinking water. There is no established Maximum 
Concentration Level (MCL) for residues of kresoxim-methyl in

[[Page 11879]]

drinking water under the Safe Drinking Water Act (SDWA).
    2. Non-dietary exposure. Kresoxim-methyl is currently registered 
for use in greenhouses on ornamental plants. The potential for non-
occupational exposure to the general population is not significant.

E. Cumulative Effects

    BASF has considered the potential for cumulative effects of 
kresoxim-methyl and other substances that have a common mechanism of 
toxicity. No evidence or information exists to suggest that toxic 
effects produced by kresoxim-methyl would be cumulative with those of 
any other chemical compound.

F. Safety Determination

    1. U.S. population. Using the conservative exposure assumptions 
described above and based on the completeness and the reliability of 
the toxicity data, BASF has estimated that aggregate exposure to 
kresoxim-methyl will utilize less than 0.15% of the RfD for the total 
U.S. population. BASF concludes that there is a reasonable certainty 
that no harm will result from the aggregate exposure to residues of 
kresoxim-methyl, including anticipated dietary exposure and non-
occupational exposures.
    2. Infants and children--i. Developmental toxicity. The 
teratogenicity study in rats resulted in a developmental toxicity NOAEL 
of 1,000 mg/kg/day, and a maternal toxicity NOAEL of 1,000 mg/kg/day. 
These NOAEL values are significantly higher than the NOAEL from the 2 
year feeding study in rats used to establish the RfD.
    The teratogenicity study in rabbits resulted in a developmental 
toxicity NOAEL of 1,000 mg/kg/day, and a maternal toxicity NOAEL of 
1,000 mg/kg/day. These NOAEL values are significantly higher than the 
NOAEL from the 2 year feeding study in rats used to establish the RfD.
    ii. Reproductive toxicity. The 2-generation reproduction study with 
rats resulted in a reproductive NOAEL of 1,625 mg/kg/day, and a 
maternal NOAEL of 100 mg/kg/day. These NOAEL values are significantly 
higher than the NOAEL from the 2 year feeding study in rats used to 
establish the RfD.
    iii. Reference Dose. Since developmental and reproductive toxicity 
occurs at levels at or above the levels shown to exhibit parental 
toxicity and since these levels are significantly higher than those 
used to calculate the RfD, BASF believes the RfD of 0.36 mg/kg/day is 
an appropriate measure of safety for infants and children.
    Using the conservative exposure assumptions described above, BASF 
has concluded that the portion of the RfD that will be utilized by 
aggregate exposure to residues of kresoxim-methyl resulting from the 
proposed tolerances will be less than 1% for all populations of infants 
and children. The most highly exposed group in the subpopulation groups 
would be non-nursing infant < 1-year old, which uses 0.88% of the RfD. 
Therefore, based on the completeness and reliability of the toxicity 
data and the conservative exposure assessment, BASF concludes that 
there is a reasonable certainty that no harm will result to infants and 
children from aggregate exposure to the residues of kresoxim-methyl, 
including all anticipated dietary exposure and all other non-
occupational exposures.

G. International Tolerances

    A maximum residue level has not been established for kresoxim-
methyl by the Codex Alimentarius Commission.
[FR Doc. 99-5823 Filed 3-9-99; 8:45 am]
BILLING CODE 6560-50-F