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pyrithiobac-sodium Pesticide Petition Filing 6/99



ENVIRONMENTAL PROTECTION AGENCY

[PF-877; FRL-6085-5]

 
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-877], must 
be received on or before August 13, 1999.
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 by following 
the instructions under ``SUPPLEMENTARY INFORMATION.'' No confidential 
business information (CBI) 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 
CBI. CBI should not be submitted through e-mail. Information marked as 
CBI will not be disclosed except in accordance with procedures set 
forth in 40 CFR part 2. A copy of the comment that does not contain CBI 
must be submitted for inclusion in the public record. Information not 
marked confidential may be disclosed publicly by EPA without prior 
notice. All written comments will be available for public inspection in 
Rm. 1132 at the address given above, from 8:30 a.m. to 4 p.m., Monday 
through Friday, excluding legal holidays.

FOR FURTHER INFORMATION CONTACT: The product manager listed in the 
table below:

[[Page 37973]]



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                                   Office location/
        Product Manager            telephone number          Address
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Eugene Wilson.................  Rm. 235, CM #2, 703-    1921 Jefferson
                                 305-6103, e-            Davis Hwy,
                                 mail:wilson.eugene@ep   Arlington, VA
                                 a.gov.
James A. Tompkins.............  Rm. 239, CM #2, 703-
                                 305-5697, e-mail:
                                 tompkins.james@epa.go
                                 v.
Bipin Gandhi..................  Rm. 713J, CM #2 703-    Do.
                                 308-8380, e-
                                 mail:gandhi.bipin@epa
                                 .gov.
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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-877] (including comments and data submitted 
electronically as described below). A public version of this record, 
including printed, paper versions of electronic comments, which does 
not include any information claimed as CBI, is available for inspection 
from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal 
holidays. The official record is located at the address in 
``ADDRESSES'' at the beginning of this document.
    Electronic comments can be sent directly to EPA at:
    opp-docket@epamail.epa.gov


    Electronic comments must be submitted as an ASCII file avoiding the 
use of special characters and any form of encryption. Comment and data 
will also be accepted on disks in Wordperfect 5.1 file format or ASCII 
file format. All comments and data in electronic form must be 
identified by the docket number [PF-877]) and appropriate petition 
number. Electronic comments on this notice may be filed online at many 
Federal Depository Libraries.

List of Subjects

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

Dated: June 25,1999.

    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.


2. E. I. DuPont de Nemours and Co., Inc.

 4F4391

    EPA has received a pesticide petition (4F4391) from DuPont, P.O. 
Box 80038, Wilmington, DE 19880-0038 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 extending time-limited tolerance 
for residues of pyrithiobac sodium salt (sodium 2-chloro-6-[(4,6-
dimethoxypyrimidin-2-yl)thio]benzoate) in or on the raw agricultural 
commodity (RAC) cottonseed at 0.02 ppm until September 30, 2001. In the 
Federal Register of October 25, 1995 (60 FR 54607) (FRL 4982-8), EPA 
established a time-limited tolerance pursuant to the FFDCA for residues 
of the herbicide pyrithiobac sodium salt in or on the RAC cottonseed at 
0.02 ppm. In the Federal Register of October 22, 1997 (62 FR 54778) 
(FRL 5746-6), EPA extended the time-limited tolerance pursuant to the 
FFDCA for residues of the herbicide pyrithiobac sodium salt in or on 
the RAC cottonseed at 0.02 ppm. This time-limited tolerance expires 
September 30, 1999. The tolerance was issued and renewed as a time-
limited tolerance because EPA required additional residue data on the 
commodity of cotton gin byproducts. 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 qualitative nature of the residues of 
pyrithiobac sodium in cotton is adequately understood. Metabolism 
studies with pyrithiobac sodium indicate the major metabolic pathway 
being o-dealkylation of the parent compound resulting in o-desmethyl 
pyrithiobac sodium (O-DPS), both free and conjugated, was the major 
metabolite identified in cotton foliage. The results of a confined crop 
rotation study with pyrithiobac sodium revealed the presence of a 
metabolite 2-chloro-6-sulfobenzoic acid (CSBA) not seen in the cotton 
metabolism study. This metabolite appeared to originate from soil 
metabolism of pyrithiobac sodium. Since preemergence applications of 
pyrithiobac sodium are allowed, crop residues of CSBA were considered a 
possibility. In consideration of PP 4F4391, Chemistry Branch Tolerance 
Support (CBTS), EPA, in consultation with the Health Effects Division 
(HED) Metabolism Committee has previously concluded that for the 
proposed use on cotton, none of the pyrithiobac sodium metabolites 
including O-DPS and CSBA warrant inclusion in the tolerance regulation, 
and that the only residue of concern is the parent, pyrithiobac sodium.
    2. Analytical method. There is a adequately validated practical 
analytical method available using HPLC-UV with column switching, to 
measure levels of pyrithiobac sodium in or on cotton with a limit of 
quantitation (LOQ) that allows monitoring of cottonseed at or above 
tolerance levels. EPA has provided information on this method to FDA 
for future publication in PAM II.
    3. Magnitude of residues. Crop field trial residue data from a 60- 
day pre-harvest interval (PHI) study shows that the established 
pyrithiobac sodium time-limited tolerance on cottonseed of 0.02 ppm 
will not be exceeded when Staple Herbicide is used as directed. An 
adequate cottonseed processing study shows that pyrithiobac sodium does 
not concentrate in cottonseed processed commodities; thus, no 
tolerances on these commodities are required.

B. Toxicological Profile

    1. Acute toxicity. Pyrithiobac sodium technical has been placed in 
EPA Toxicity Category II for acute eye irritation based on the test 
article inducing irritation in the form of corneal opacity, iritis and 
conjunctival redness, and discharge in the eyes of rabbits after 
receiving ocular doses of 36 mg (0.1 ml). Signs of irritation were 
clear within 14-days of treatment. Pyrithiobac sodium has been placed 
in Toxicity Category III for acute dermal toxicity based on the test 
article being nonlethal and nonirritating at the limit dose (LTD) of 
2,000 milligrams/kilograms (mg/kg) highest dose tested (HDT). 
Pyrithiobac sodium has been placed in Toxicity Category III for acute 
oral toxicity based on acute oral LD<INF>50</INF> of 3,200 mg/kg for 
both male and female (M/F) rats. Pyrithiobac sodium has been placed in 
Category IV for the remaining acute toxicity tests based on the 
following: a rat acute inhalation study with an LC<INF>50</INF> of > 
6.9 milligrams/per liter (mg/l); and a primary dermal irritation test 
that did not induce a dermal irritation response. A dermal 
sensitization test with pyrithiobac sodium technical in guinea pigs 
demonstrated no significant effects. Based on these results, 
pyrithiobac sodium does not pose an acute dietary or exposure risk.
    2. Genotoxicity. Pyrithiobac sodium technical was negative (non-
mutagenic and non-genotoxic) in the following tests: Ames microbial 
mutation assay; the hypoxanthine-guanine phosphoribosyl transferase 
gene mutation assay using Chinese hamster ovary cells; and induction of 
unscheduled DNA synthesis (UDS) in primary rat hepatocytes. Pyrithiobac 
sodium was positive in an in vitro assay for chromosome aberrations in 
human lymphocytes. It was negative for the induction of micronuclei in 
the bone marrow cells of M/F CD-1 mice administered the test article by 
oral gavage at 500, 1,000 or 2,000 mg/kg. Based on the weight of these 
data, pyrithiobac sodium is neither genotoxic nor mutagenic.
    3. Reproductive and developmental toxicity. A 2-generation, 4 
litter reproduction study with CD rats treated at dietary levels of 0, 
25, 1,500, 7,500 or 20,000 ppm of pyrithiobac sodium demonstrated a 
maternal no observed adverse effect level (NOAEL) of 1,500 ppm (103 mg/
kg/day) and a maternal lowest observed adverse effect level (LOAEL) of 
7,500 ppm (508 mg/kg/day), based on decreased body weight (bwt) gain 
and food efficacy. An offspring NOAEL of 7,500 ppm (508 mg/kg/day) and 
LOAEL of 20,000 ppm (1,551 mg/kg/day) were also demonstrated based on 
decreased offspring bwt. Pyrithiobac sodium was not teratogenic when 
administered to rats or rabbits.
    A developmental toxicity study with pyrithiobac sodium in rats 
demonstrated a maternal NOAEL of 200 mg/kg and LOAEL of 600 mg/kg due 
to increased incidence of salivation.
    A developmental NOAEL of 600 mg/kg and LOAEL of 1,800 mg/kg were 
demonstrated based on an increased incidence of skeletal variations.
    A developmental toxicity study with pyrithiobac sodium in rabbits 
demonstrated maternal and developmental NOAELs of 300 mg/kg and a 
maternal LOAEL of 1,000 mg/kg based on mortality, decreased bwt gain 
and feed consumption, increased incidence of clinical signs, and an 
increase in early resorptions. A developmental LOAEL of 1,000 mg/kg was 
based on decreased fetal bwt gain. Based on the weight of these data, 
pyrithiobac sodium is not considered a reproductive or developmental 
hazard.
    4. Subchronic toxicity. In a 90-day feeding study in rats conducted 
with pyrithiobac sodium at dietary levels of 0, 10, 50, 500, 7,000 and 
20,000 ppm, the NOAEL was 500 ppm (31.8 and 40.5 mg/kg/day, Ms and Fs 
and the LOAEL

[[Page 37975]]

was 7,000 ppm (466 and 588 mg/kg/day, Ms/Fs) based on decreased bwt 
gains and increased rate of hepatic B-oxidation in Ms.
    In a 90-day feeding study in mice conducted with pyrithiobac sodium 
at dietary levels of 0, 10, 50, 500, 1,500 and 7,000 ppm, the NOAEL was 
500 ppm (83.1 and 112 mg/kg/day, Ms/Fs) and the L0AEL was 1,500 ppm 
(263 and 384 mg/kg/day, Ms/Fs) based on increased liver weight and 
increased incidence of hepatocellular hypertrophy in Ms and decreased 
neutrophil count in Fs.
    In a 90-day feeding study in dogs conducted with pyrithiobac sodium 
at dietary levels of 0, 50, 5,000, or 20,000 ppm, the NOAEL was 5,000 
ppm (165 mg/kg/day) and the LOAEL was 20,000 ppm (626 mg/kg/day) based 
on decreased red blood cell count, hemoglobin, and hematocrit in 
females and increased liver weight in both sexes.
    In a 21-day dermal study with rats conducted with pyrithiobac 
sodium at exposure levels of 0, 50, 500, or 1,200 mg/kg/day, the dermal 
irritation NOAEL was 500 mg/kg/day and the dermal irritation LOAEL was 
1,200 mg/kg/day. There were no systemic effects observed at this high 
dose; therefore, the systemic NOAEL is considered to be 1,200 mg/kg/
day.
    5. Chronic toxicity. A 1-year feeding study in dogs conducted with 
pyrithiobac sodium at dietary levels of 0, 100, 5,000, and 20,000 ppm 
resulted in a NOAEL of 5,000 ppm (143 and 166 mg/kg/day, Ms/Fs) and a 
LOAEL of 20,000 ppm (580 and 647 mg/kg/day, Ms/Fs) based on decreases 
in bwt gain and increased liver weight.
    A 78-week oncogenicity study in mice was conducted with pyrithiobac 
sodium at dietary levels of 0, 10, 150, 1,500 and 5,000 ppm. The 
systemic NOAEL is 1,500 ppm (217 and 319 mg/kg/day, Ms/Fs) and the 
LOAEL is 5,000 ppm (745 and 1,101 mg/kg/day, Ms/Fs), based on decreased 
bwt gain and liver lesions. Kidney effects were also observed at 5,000 
ppm; however, these were present at low incidence and were of minimal 
severity and were considered to be of only minimal biological 
significance. Increased incidence of foci/focus of hepatocellular 
alteration was observed in males fed 5,000 ppm diets. Increased 
incidences of hepatocellular neoplasms (adenomas or adenomas plus 
carcinomas) were observed only in 150 and 1,500 ppm Ms. The incidence 
of these liver tumors was not significantly increased in the 5,000 ppm 
Ms or in Fs at any dose level; the 5,000 ppm male tumor incidence was 
within the historical control range.
    A 2-year study in rats was conducted at dietary pyrithiobac sodium 
levels of 0, 5, 25, 1,500 or 5,000 ppm for Ms and 0, 5, 25, 5,000 or 
15,000 ppm for Fs. The NOAEL for systemic effects was 1,500 ppm (58.7 
mg/kg/day) for Ms and 5,000 ppm (278 mg/kg/day) for Fs. The lowest 
effect level (LEL) was 5,000 ppm (200 mg/kg/day for Ms)/15,000 ppm (918 
mg/kg/day) for Fs. The LEL was based on the following: decreased bwt 
gain, and food efficiency (for Fs); mild changes in hematology and 
urinalysis, clinical signs indicative of urinary tract dysfunction 
(both sexes); increased incidence of focal cystic degeneration in the 
liver and increased rate of hepatic peroxisome beta-oxidation (Ms); and 
an increased incidence of inflammatory and degenerative microscopic 
lesions in the kidney (Fs). There was evidence of oncogenicity based on 
an increased trend for kidney tubular combined adenoma/carcinoma on 
male rats and an increased trend for kidney tubular adenomas in female 
rats. Although the incidences were low, they were statistically 
significant. The highest dose level tested (HDLT) in male rats (5,000 
ppm) was considered adequate for assessment of oncogenic potential, 
that in female rats (15,000 ppm) exceeded the maximum tolerated dose 
(MTD).
    6. Carcinogenicity. In consideration of PP 4F4391, the HED 
Carcinogenicity Peer Review Committee has previously concluded that the 
available data provide limited evidence of the carcinogenicity of 
pyrithiobac sodium in mice and rats and has classified pyrithiobac 
sodium as a Group C (possible human carcinogen with limited evidence of 
carcinogenicity in animals) in accordance with Agency guidelines 
published in the Federal Register of September 24, 1986 (51 FR 33992) 
and recommend that for the purpose of risk characterization a low-dose 
extrapolation model should be applied to the experimental animal tumor 
data for quantification for human risk (Q1*). This decision was based 
on liver adenomas, carcinomas and combined adenoma/carcinomas in the 
male mouse and kidney tubular adenomas, carcinomas and combined 
adenoma/carcinomas in the male rat. The unit risk, Q1* (mg/kg/day)-
<SUP>1</SUP>, of pyrithiobac sodium is 1.05 x 10-<SUP>3</SUP> (mg/kg/
day)-<SUP>1</SUP> in human equivalents based on male kidney tumors.
    7. Animal metabolism. Disposition and metabolism of pyrithiobac 
sodium were tested in M/F rats using two radio-labeled forms of 
pyrithiobac sodium. Either phenyl-labeled or pryimidine-labeled 
compounds were administered orally at 5 or 250 mg/kg. In addition, 
intravenous administration was evaluated at 5 mg/kg. Essentially all of 
the dose was excreted in the urine and feces, with greater than 90% 
being excreted within 48 hours. No label was detected in the expired 
air. Only minute quantities of radioactivity (at or near the limit of 
detection (LOD)) were detected in the major organs of metabolism and 
excretion. This study indicates that pyrithiobac sodium has low 
toxicity and does not accumulate within the body. The major compound 
eliminated in urine and feces was O-DPS (desmethyl metabolite), formed 
by demethylation of the pyrimidine ring. There was evidence that 
conjugation with glucuronic acid and 5-hydroxylation of the pyrimidine 
ring of pyrithiobac sodium were additional minor routes of metabolism 
in the rat.
    The ruminant metabolism of pyrithiobac sodium was studied in 
lactating goats fed at a level of 15 mg/kg for 5 consecutive days, 
equaling a dose greater than 1,000 times the anticipated residues of 
pyrithiobac sodium and its metabolites in cottonseed, and greater than 
100 times the anticipated residues in cotton gin byproducts. Seventy-
six to 80% of the total administered dose was recovered in the excreta 
plus cage washes. Concentrations of radioactivity in milk, muscle, fat, 
whole-blood, and plasma were negligible. Biotransformation of the 
parent compound was not substantial with 90% of urine radioactivity and 
40% of fecal extract corresponding to parent test substance. The major 
biotransformation pathway was O-demethylation. The results of this 
study indicate low potential for transfer of residues of pyrithiobac 
sodium and/or its metabolites into edible tissues or milk of ruminants, 
even at highly exaggerated feeding levels.
    8. Metabolite toxicology. There is no evidence that the metabolites 
of pyrithiobac sodium as identified in either the plant metabolism, 
confined crop rotation, or animal metabolism studies are of any 
toxicological significance.
    9. Neurotoxicity. A 90-day rat neurotoxicity screen battery 
conducted with pyrithiobac sodium resulted in a systemic NOAEL of 7,000 
ppm (466 and 588 mg/kg/day, Ms/Fs) and a systemic LOAEL of 20,000 ppm 
(1,376 and 1,609 mg/kg/day, Ms/Fs) based on reduced bwt gain and food 
efficiency and increased liver weight. Slight reductions in hind-leg 
grip strength and slightly increased foot splay in Ms were observed in 
20,000 ppm Ms. However, because these were of small magnitude, lacked 
statistical significance, and corresponding histopathology,

[[Page 37976]]

pyrithiobac sodium was not considered a neurotoxin. The NOAEL for 
neurotoxicity was 20,000 ppm highest dose tested (HDT).
    10. Endocrine disruption. No special studies investigating 
potential estrogenic or other endocrine effects of pyrithiobac sodium 
have been conducted. However, the standard battery of required 
toxicology studies has been completed and found acceptable. These 
include an evaluation of the potential effects on reproduction and 
development, and an evaluation of the pathology of the endocrine organs 
following repeated or long-term exposure to doses that far exceed 
likely human exposures. Based on these studies there is no evidence to 
suggest that pyrithiobac sodium has an adverse effect on the endocrine 
system.

C. Aggregate Exposure

    1. Dietary exposure--i. Food. For purposes of assessing the 
potential dietary exposure under this tolerance, an estimate of 
aggregate exposure is made using the tolerance on cottonseed at 0.02 
ppm. The potential exposure is obtained by multiplying the tolerance 
level residues by the consumption data which estimates the amount of 
cottonseed products translated as cottonseed meal and cottonseed oil 
eaten by various population subgroups. Cottonseed is fed to animals, 
thus exposure of humans to residues of cottonseed might result if such 
residues are transferred to meat, milk, poultry, or eggs. However, in 
consideration of PP 4F4391, CBTS has previously concluded that 
secondary residues in meat, milk, poultry, and eggs are not expected 
from the use of cottonseed (undelinted) as an animal feed. There are no 
other established tolerances or registered uses for pyrithiobac sodium 
in the United States. Based on a NOAEL of 58.7 mg/kg/day, from the 
chronic rat toxicity study and a 100-fold safety factor, the reference 
dose (RfD) is 0.58 mg/kg/day. Assuming residues at tolerance levels and 
that 100% of the crop is being treated, a theoretical maximum residue 
contribution (TMRC) of > 0.000001 mg/kg/day is calculated. With the 
above assumptions which clearly overestimate potential human exposure 
and are a most conservative assessment of risk, dietary (food) exposure 
to pyrithiobac sodium will utilize significantly less than 1% of the 
RfD for the overall U.S. population. For the most highly exposed 
subgroup, children aged 1-6 years, the TMRC is 0.000001 mg/kg/day, 
which is still less than 1% of the RfD. The unit risk, Q1* (mg/kg/day)-
<SUP>1</SUP>, of pyrithiobac sodium is 1.05 x 10-<SUP>3</SUP> (mg/kg/
day-<SUP>1</SUP> in human equivalents based on male kidney tumors. 
Based on this upper bound potency factor (Q1*), a 70-year life span, 
and the assumption that 100% of the crop is treated with pyrithiobac 
sodium, the upper-bound limit of a dietary carcinogenic risk is 
calculated in the range of one incidence in a billion (1.0 x 10-
<SUP>9</SUP>).
    ii. Drinking water. Other potential dietary sources of exposure of 
the general population to pesticides are residues in drinking water. 
There is no maxium concentration level (MCL) established for residues 
of pyrithiobac sodium. The petitioner has reported to the Environmental 
Fate and Ground Water (EFGWB) branch of EPA the interim results of a 
prospective ground water monitoring study conducted at a highly 
vulnerable site. In consideration of this information in support of PP 
4F4391, EFGWB has previously concluded by preliminary evaluation, that 
pyrithiobac sodium may not be stable enough to leach to ground water at 
most use sites, even in sandy soils. All other environmental fate data 
requirements for pyrithiobac sodium have been satisfied and based on 
these studies and the conditions of use, the potential for finding 
pyrithiobac sodium residues in drinking water is minimal.
    2. Non-dietary exposure. Pyrithiobac sodium is not registered for 
any use which could result in non-occupational, non-dietary exposure to 
the general population.

D. Cumulative Effects

    Pyrithiobac sodium is based on a new chemical class; there are no 
known registered herbicides with similar structure. Therefore, EPA 
should consider only the potential risks of pyrithiobac sodium in its 
exposure assessment. The herbicidal activity of pyrithiobac sodium is 
due to the inhibition of acetolactate synthase (ALS), an enzyme only 
found in plants. ALS is part of the biosynthetic pathway leading to the 
formation of branched chain amino acids. Animals lack ALS and this 
biosynthetic pathway. This lack of ALS contributes to the low toxicity 
of pyrithiobac sodium in animals. There is no evidence to indicate or 
suggest that pyrithiobac sodium has any toxic effects on mammals that 
would be cumulative with those of any other chemical.

E. Safety Determination

    1. U.S. population. Based on a complete and reliable toxicity data 
base, the EPA has adopted an RfD value of 0.58 mg/kg/day using the 
NOAEL of 58.7 mg/kg/day, from the 2-year chronic toxicity study in rats 
and a 100-fold safety factor. Using crop tolerance levels and assuming 
100% of the crop being treated a TMRC was calculated for the overall 
U.S. population and 22 population subgroups. This analysis concluded 
that aggregate exposure to pyrithiobac sodium will utilize 
significantly less that 1% of the RfD for either the entire U.S. 
population or any subgroup population. The TMRC for the most highly 
exposed subgroup identified as children aged 1-6 years was 0.000001 mg/
kg/day. EPA generally has no concern for exposure 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 risk to 
human health. Thus, there is a reasonable certainty that no harm will 
result from aggregate exposure to pyrithiobac sodium residues. The unit 
risk, Q1* (mg/kg/day)-<SUP>1</SUP>, of pyrithiobac sodium is 1.05 x 10-
<SUP>3</SUP> (mg/kg/day)-<SUP>1</SUP> in human equivalents based on 
male kidney tumors. Based on this upper bound potency factor (Q1*) and 
assuming a 70-year lifetime exposure an upper-bound limit of a dietary 
carcinogenic risk is calculated in the range of one incidence in a 
billion (1.0 x 10-<SUP>9</SUP>). This indicates a negligible cancer 
risk.
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of pyrithiobac sodium, 
data from the previously discussed developmental and reproduction 
toxicity studies were considered. Developmental studies are designed to 
evaluate adverse effects on the developing organism resulting from 
pesticide exposure during prenatal development. Reproduction studies 
provide information relating to reproductive and other effects on 
adults and offspring from prenatal and postnatal exposure to the 
pesticide. Based on the weight of these data, pyrithiobac sodium was 
not a reproductive toxicant. Maternal and developmental effects 
NOAEL's, LOAEL's were comparable indicating no increase in 
susceptibility of developing organisms. No evidence of endocrine 
effects were noted in any study. FFDCA section 408 provides that EPA 
may apply an additional safety factor for infants and children in the 
case of threshold effects to account for prenatal and postnatal 
toxicity and the completeness of the data base. Based on current 
toxicological data requirements, the data base for pyrithiobac sodium 
relative to prenatal and postnatal effects for children is complete. 
The NOAEL of 58.7 mg/kg/day from the 2-year rat study with pyrithiobac 
sodium, which was used to calculate the RfD, is lower than any of the 
NOAEL's defined in the

[[Page 37977]]

developmental and reproductive toxicity studies with pyrithiobac 
sodium. When the weight of these facts is considered, an additional 
safety factor is not warranted for developmental effects. As stated 
above, aggregate exposure assessments utilized significantly less than 
1% of the RfD for either the entire U.S. population or any of 22 
population subgroups including infants and children. Therefore, it may 
be concluded that there is reasonable certainty that no harm will 
result to infants and children from aggregate exposure to pyrithiobac 
sodium residues.

F. International Tolerances

    There are no established Codex MRLs for pyrithiobac sodium on 
cottonseed. An established Mexican tolerance for pyrithiobac sodium on 
cottonseed is identical to the United States tolerance. Compatibility 
is not a problem at this time.

[FR Doc. 99-17317 Filed 7-13-99; 8:45 am]
BILLING CODE 6560-50-F