[Federal Register Volume 62, Number 185 (Wednesday, September 24, 1997)]
[Notices]
[Pages 49979-49983]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-25234]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-764; FRL-5745-8]


 E.I. DuPont de Nemours and Co., Inc.; Pesticide Tolerance 
Petition Filing

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

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SUMMARY: This notice announces the initial filing of a pesticide 
petition proposing the establishment of regulations for residues of a 
certain pesticide chemical in or on various food commodities.
DATES: Comments, identified by the docket control number PF-764, must 
be received on or before October 24, 1997.
ADDRESSES: By mail submit written comments to: Information and Records 
Integrity Branch, Public Information and Services Division (7506C), 
Office of Pesticides Programs, Environmental Protection Agency, 401 M 
St., SW., Washington, DC 20460. In person bring comments to: Rm. 1132, 
CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
    Comments and data may also be submitted electronically by following 
the instructions under ``SUPPLEMENTARY INFORMATION.'' No confidential 
business information should be submitted through e-mail.
    Information submitted as a comment concerning this document may be 
claimed confidential by marking any part or all of that information as 
``Confidential Business Information'' (CBI). CBI should not be 
submitted through e-mail. Information marked as CBI will not be 
disclosed except in accordance with procedures set forth in 40 CFR part 
2. A copy of the comment that does not contain CBI must be submitted 
for inclusion in the public record. Information not marked confidential 
may be disclosed publicly by EPA without prior notice. All written 
comments will be available for public inspection in Rm. 1132 at the 
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday, 
excluding legal holidays.

FOR FURTHER INFORMATION CONTACT: James Stone, PM-25 Team, 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. 257, Crystal Mall 
#2 1921 Jefferson Davis Highway, Arlington, VA 22202, (703) 305-7391; 
e-mail: [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-764] (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 control number (PF-764) 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: September 11, 1997.

Peter Caulkins,

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.

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

PP 4F4391

    EPA has received a pesticide petition (PP 4F4391) from E.I. DuPont 
de Nemours and Co., Inc (DuPont), Barley Mill Plaza, P.O. Box 80083, 
Wilmington, DE 19880-0038 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 pyrithiobac sodium 
salt (sodium 2-chloro-6-[(4,6-dimethoxypyrimidin-2-yl)thio]benzoate) in 
or on the raw agricultural commodities cottonseed at 0.02 part per 
million (ppm) and cotton gin byproducts at 0.10 (ppm). The proposed 
analytical method involves homogenization, filtration, partition and 
cleanup with analysis by using ultraviolet detection. 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.

[[Page 49980]]

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). 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 CBTS, in 
consultation with the 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 are independently validated practical 
analytical methods available using liquid chromatography (HPLC) with 
column switching and ultraviolet (UV) detection, to measure levels of 
pyrithiobac sodium in or on cottonseed and cotton gin byproducts, with 
limits of quantitation that will allow for monitoring of crop residues 
at or above tolerance levels. EPA has previously provided information 
on the method for cottonseed to FDA for future publication in PAM II.
    3. Magnitude of residues. Crop field trial residue data from 60 day 
PHI studies show that the proposed pyrithiobac sodium tolerances on 
these raw agricultural commodities will not be exceeded when 
pyrithiobac sodium is used as directed. An adequate cottonseed 
processing study shows that pyrithiobac sodium does not concentrate in 
cottonseed processed commodities. No tolerances on processed 
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 of 2,000 
mg/kg, the highest dose tested (HDT). Pyrithiobac sodium has been 
placed in Toxicity Category III for acute oral toxicity based on acute 
oral LD50s of 3,200 mg/kg for both male and female 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 LC50 of > 6.9 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. Genotoxicty. 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 male and female 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 two 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 NOEL of 1,500 ppm (103 mg/kg/day) and a maternal LOEL of 7,500 
ppm (508 mg/kg/day), based on decreased body weight gain and food 
efficacy. An offspring NOEL of 7,500 ppm (508 mg/kg/day) and LOEL of 
20,000 ppm (1,551 mg/kg/day) were also demonstrated based on decreased 
offspring body weight. Pyrithiobac sodium was not teratogenic when 
administered to rats or rabbits.
    A developmental toxicity study with pyrithiobac sodium in rats 
demonstrated a maternal NOEL of 200 mg/kg and LOEL of 600 mg/kg due to 
increased incidence of salivation. A developmental NOEL of 600 mg/kg 
and LOEL 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 NOELs of 300 mg/kg and a 
maternal LOEL of 1,000 mg/kg based on mortality, decreased body weight 
gain and feed consumption, increased incidence of clinical signs, and 
an increase in early resorptions. A developmental LOEL of 1,000 mg/kg 
was based on decreased fetal body weight 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 NOEL was 500 ppm (31.8 and 40.5 mg/kg/day, m/f and the 
LOEL was 7,000 ppm (466 and 588 mg/kg/day, m/f) based on decreased body 
weight gains and increased rate of hepatic B-oxidation in males.
    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 NOEL was 
500 ppm (83.1 and 112 mg/kg/day, m/f) and the L0EL was 1,500 ppm (263 
and 384 mg/kg/day, m/f) based on increased liver weight and increased 
incidence of hepatocellular hypertrophy in males and decreased 
neutrophil count in females.
    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 NOEL was 5,000 
ppm (165 mg/kg/day) and the LOEL 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 NOEL was 500 mg/kg/day and the dermal irritation LOEL was 
1,200 mg/kg/day. There were no systemic effects observed at this high 
dose; therefore, the systemic NOEL 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 NOEL of 5,000 ppm (143 and 166 mg/kg/day, m/f) and a LOEL 
of 20,000 ppm (580 and 647 mg/kg/day, m/f) based on decreases in body 
weight 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

[[Page 49981]]

NOEL is 1,500 ppm (217 and 319 mg/kg/day, m/f) and the LEL is 5,000 ppm 
(745 and 1,101 mg/kg/day, m/f), based on decreased body weight 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 males. The incidence of these liver 
tumors was not significantly increased in the 5,000 ppm males or in 
females 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 males and 0, 5, 25, 5,000 or 
15,000 ppm for females. The NOEL for systemic effects was 1,500 ppm 
(58.7 mg/kg/day) for males and 5,000 ppm (278 mg/kg/day) for females. 
The LEL was 5,000 ppm (200 mg/kg/day for males)/15,000 ppm (918 mg/kg/
day) for females. The LEL was based on the following: decreased body 
weight, body weight gain and food efficiency (for females); mild 
changes in hematology and urinalysis, clinical signs indicative of 
urinary tract dysfunction (both sexes); increased incidence of focal 
cystic degereration in the liver and increased rate of hepatic 
peroxisome beta-oxidation (males); and an increased incidence of 
inflammatory and degenerative microscopic lesions in the kidney 
(females). There was evidence of oncogenicity based on an increased 
trend for kidney tubular combined adenoma/carcinoma in 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 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).
    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 in 1986 (51 FR 33992, Sept. 24, 1986) 
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)-1, of pyrithiobac sodium is 1.05  x  10-3 
(mg/kg/day)-1 in human equivalents based on male kidney tumors.
    6. Animal metabolism. Disposition and metabolism of pyrithiobac 
sodium were tested in male and female rats using two radiolabeled forms 
of pyrithiobac sodium. Either phenyl-labeled or pryimidine-labeled 
compounds were administered orally at 5 or 250 mg/kg. In addition, i.v. 
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) 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 1000 times the anticipated residues of 
pyrithiobac sodium and its metabolites in cottonseed, and greater than 
100 times the anticipated residues in cotton gin byproducts. Of the 
total administered dose 76-80% was recovered in the excreta plus 
cagewashes. 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.
    7. 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.
    i. Neurotoxicity. A 90-day rat neurotoxicity screen battery 
conducted with pyrithiobac sodium resulted in a systemic no observed-
effect level (NOEL) of 7,000 ppm (466 and 588 mg/kg/day, m/f) and a 
systemic lowest-observed-effect level (LOEL) of 20,000 ppm (1,376 and 
1,609 mg/kg/day, m/f) based on reduced body weight gain and food 
efficiency and increased liver weight. Slight reductions in hind-leg 
grip strength and slightly increased foot splay in males were observed 
in 20,000 ppm males. However, because these were of small magnitude, 
lacked statistical significance and corresponding histopathology, 
pyrithiobac sodium was not considered a neurotoxin. The NOEL for 
neurotoxicity was 20,000 ppm (HDT).
    ii. Endocrine effects. 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. It is proposed that pyrithiobac sodium be 
defined as the residue for enforcement purposes. Monitoring for 
pyrithiobac sodium residues in field samples will provide an adequate 
estimate of this compound in edible portions of treated crops.
    2. Food--i. acute dietary exposure. A Tier I acute dietary exposure 
analysis was conducted using the Dietary Exposure Evaluation Model 
(DEEM ver. 5.10) and assuming tolerance level residues for cottonseed 
oil, cottonseed meal, and a very conservative residue value of 6 parts 
per billion (ppb) for all sources of dietary water. Using the acute 
endpoint of 200 mg/kg from a developmental toxicity study in rats, the 
margins of exposure were greater than 100,000 for all 22 population 
subgroups at the 95th percentile exposure.

[[Page 49982]]

    ii. Chronic dietary exposure. For purposes of assessing the 
potential chronic dietary exposure under this tolerance, an estimate of 
aggregate exposure is made using the proposed tolerance on cottonseed 
at 0.02 ppm, cotton gin byproducts at 0.10 ppm, and a very conservative 
contribution from drinking water based on GENEEC modeling. 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 and cotton gin 
byproducts are fed to animals, thus exposure of humans to residues of 
pyrithiobac sodium might result if such residues are transferred to 
meat, milk, poultry, or eggs. However, in previous consideration of PP 
4F4391 CBTS has concluded that secondary residues in meat, milk, 
poultry and eggs are not expected from the use of cottonseed as an 
animal feed. A ruminant (goat) metabolism study further demonstrates 
that residues of pyrithiobac sodium in cotton gin byproducts will not 
result in secondary meat or milk residues when this commodity is fed to 
livestock. There are no other established tolerances or registered uses 
for pyrithiobac sodium in the United States. Based on a NOEL 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 < 0.1 mg/kg/day is 
calculated using the DEEM computer software (version 5.1, Novigen 
Sciences, Inc., 1997). 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, non-nursing infants 
less than 1 year old, the TMRC is also < 0.1 mg/kg/day, which is still 
less than 1% of the RfD. The unit risk, Q1* (mg/kg/
day)-1, of pyrithiobac sodium is 1.05  x  10-3 
(mg/kg/day)-1 in human equivalents based on male kidney 
tumors. Based on this upper bound potency factor (Q*), a 70-
year lifespan, 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 1 incidence in a billion (1.0  x  
10-9).
    3. Drinking water . Other potential dietary sources of exposure of 
the general population to pesticides are residues in drinking water. 
There is no Maximum Contaminant Level established for residues of 
pyrithiobac sodium. The petitioner has reported to the Environmental 
Fate and Groundwater Branch of EPA (EFGWB) the results of a prospective 
groundwater monitoring study conducted at a highly vulnerable site. 
This study confirms the previous interim conclusions of EFGWB that 
pyrithiobac sodium may not be stable enough to leach to groundwater at 
most use sites, even in sandy soils. The potential for pyrithiobac 
sodium to enter surface water is also very low. This is supported by 
modeling done using GENEEC which under worst case conditions (100% of 
area treated, long half-life, etc.) predicted peak surface water 
concentrations of only 6 ppb. All environmental fate data requirements 
for pyrithiobac sodium have now been satisfied and based on these 
studies, the conditions of use, and worst-case modeling, the potential 
for finding pyrithiobac sodium residues in drinking water is minimal.
    4. 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 
database, the EPA has adopted an RfD value of 0.58 mg/kg/day using the 
NOEL 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 treated, a Theoretical Maximum Residue Contribution 
(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 than 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 non-nursing 
infants less than 1 year old was also < 0.1 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)-1, of pyrithiobac sodium is 1.05  x  
10-3 (mg/kg/day)-1 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 1 incidence in a billion (1.0  x  10-9). 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 pre-natal development. Reproduction studies 
provide information relating to reproductive and other effects on 
adults and offspring from pre-natal and post-natal exposure to the 
pesticide. Based on the weight of these data, pyrithiobac sodium was 
not a reproductive toxicant. Maternal and developmental effects 
(NOEL's, LOEL'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 pre and post-natal toxicity 
and the completeness of the database. Based on current toxicological 
data requirements, the database for pyrithiobac sodium relative to pre- 
and post-natal effects for children is complete. The NOEL 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 NOEL's defined in 
the developmental and reproductive toxicity studies with pyrithiobac

[[Page 49983]]

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 U.S. tolerance. Compatibility is not a 
problem at this time.

[FR Doc. 97-25234 Filed 9-23-97; 8:45 am]
BILLING CODE 6560-50-F