[Federal Register Volume 63, Number 44 (Friday, March 6, 1998)]
[Notices]
[Pages 11240-11252]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-5985]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-798; FRL-5777-5]


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 agricultural commodities.

DATES: Comments, identified by the docket control number PF-798, must 
be received on or before April 6, 1998.

ADDRESSES: By mail submit written comments to: Public Information and 
Records Integrity Branch, Information Resources 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 to: opp-
[email protected]. 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 given above, from 8:30 a.m. to 4 p.m., Monday through Friday, 
excluding legal holidays.

FOR FURTHER INFORMATION CONTACT: By mail: Joseph Tavano, Product 
Manager (PM) 10, 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. 
214, CM#2, 1921 Jefferson Davis Hwy., Arlington, VA. 22202, (703) 305-
6411; e-mail: [email protected].

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 raw 
agricultural 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 grantinig of the petition. Additional data may be needed 
before EPA rules on the petition.
    The official record for this notice, as well as the public version, 
has been established for this notice of filing under docket control 
number PF-798 (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,

[[Page 11241]]

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-798 and appropriate petition 
number. Electronic comments on this notice may be filed online at many 
Federal Depository Libraries.
    Authority: 21 U.S.C. 346a.

List of Subjects

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

    Dated: March 2, 1998.

Peter Caulkins,

Acting Director, Registration Division, Office of Pesticide Programs.

Summaries of Petitions

    Below summaries of the pesticide petitions are printed. The 
summaries of the petitions were prepared by the petitioners. 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. Rohm and Haas Company

PP 3G4274

    EPA has received a pesticide petition (PP 3G4274)from Rohm and Haas 
Company, 100 Independence Mall West, Philadelphia, PA 19106-2399. 
proposing pursuant to section 408(d) of the Federal Food, Drug and 
Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR part 180 by 
establishing a tolerance for residues of triazamate [Acetic acid, [{1-
{(dimethylamino) carbonyl}-3-(1,1-dimethylethyl)-1H-1,2,4-triazol-5-y1} 
thio]-,ethyl ester] and its metabolite Acetic acid,[{1-{(dimethylamino) 
carbonyl}-3-(1,1-dimethylethyl)-1H-1,2,4-triazol-5-y1}thio]-(code 
number RH-0422 in or on the raw agricultural commodity fresh apples at 
0.1 parts per million (ppm). EPA has determined that the petition 
contains data or information regarding the elements set forth in 
section 408(d)(2) of the FFDCA; however, EPA has not fully evaluated 
the sufficiency of the submitted data at this time or whether the data 
supports granting of the petition. Additional data may be needed before 
EPA rules on the petition.

A. Residue Chemistry

    1. Plant metabolism. The metabolism of triazamate in plants 
(apples) is adequately understood for the purposes of this tolerance. 
The metabolism of triazamate involves oxidative demethylation of the 
carbamoyl group. Parent compound is rapidly metabolized and is either 
not found or found at trace levels in apples. The majority of the total 
dosage is present as other non-cholinesterase inhibiting metabolites 
whose structures do not contain the dimethylcarbamoyl moiety. Because 
the proposed experimental use program is for fresh apples, livestock 
metabolism studies are not required. Tolerances for residues of 
triazamate should be expressed as the total residue from triazamate and 
its only cholinesterase-inhibiting metabolite RH-0422.
    2. Analytical method. The metabolism of triazamate in plants 
(apples) is adequately understood for the purposes of this tolerance. 
The metabolism of triazamate involves oxidative demethylation of the 
carbamoyl group. Parent compound is rapidly metabolized and is either 
not found or found at trace levels in apples. The majority of the total 
dosage is present as other non-cholinesterase inhibiting metabolites 
whose structures do not contain the dimethylcarbamoyl moiety. Because 
the proposed experimental use program is for fresh apples, livestock 
metabolism studies are not required. Tolerances for residues of 
triazamate should be expressed as the total residue from triazamate and 
its only cholinesterase-inhibiting metabolite RH-0422.
    3. Magnitude of residues. A total of 14 field residue trials in 
apples was conducted with a 25WP formulation in geographically 
representative regions of the U.S. Three applications were made at 
either 0.25 or 0.38 lb. a.i./acre. Fruit were harvested at 40 days 
after the last application. Only trace residues of triazamate were 
detected and residues of RH-0422 did not exceed 0.06 ppm.

B. Toxicological Profile

    1. Acute toxicity. Triazamate is a moderately toxic cholinesterase 
inhibitor belonging to the carbamate class. Triazamate Technical was 
moderately toxic to rats following a single oral dose (LD50 
= 50-200 milligram/kilograms (mg/kg)), and after a 4-hr inhalation 
exposure (LC50 value of >0.47 mg/L); and was minimally to 
slightly toxic to rats following a single dermal dose (LD50 
>5,000 mg/kg). In a guideline acute neurotoxicity study with triazamate 
in the rat, the NOEL for clinical signs was 5 mg/kg based on the 
observation of cholinergic signs in 1 of 10 male rats at 25 mg/kg. 
Triazamate was practically non-irritating to the skin, moderately 
irritating to eyes in rabbits and did not produce delayed contact 
hypersensitivity in the guinea pig.
    2. Genotoxicity. Triazamate is not mutagenic or genotoxic. 
Triazamate Technical was negative (non-mutagenic) in an Ames assay with 
and without hepatic enzyme activation. Triazamate Technical was 
negative in a hypoxanthine guanine phophoribosyl transferase (HGPRT) 
gene mutation assay using Chinese hamster ovary (CHO) cells in culture 
when tested with and without hepatic enzyme activation. In isolated rat 
hepatocytes, triazamate did not induce unscheduled DNA synthesis (UDS) 
or repair when tested up to the maximum soluble concentration in 
culture medium. Triazamate did not produce chromosome aberrations in an 
in vitro assay using Chinese hamster ovary cells (CHO) or an in vivo 
mouse micronucleus assay.
    3. Reproductive and developmental toxicity. In a developmental 
toxicity study in rats with Triazamate Technical, the no-observed-
effect-level (NOEL) for developmental toxicity was 64 mg/kg (highest 
dose tested) (HDT). The NOEL for maternal toxicity was 16 mg/kg based 
on clinical signs of cholinergic toxicity at 64 mg/kg.
    In a developmental toxicity study in rabbits with Triazamate 
Technical, the NOEL for developmental toxicity was 10 mg/kg (HDT). The 
NOEL for maternal toxicity was 0.5 mg/kg based on clinical signs and 
decreased body weight at 10 mg/kg.
    In a 2-generation reproduction study in rats with Triazamate 
Technical, the NOEL for reproductive effects was 1,500 ppm (101 and 132 
milligram/kilograms/day (mg/kg/day) for males and females, 
respectively; HDT). The NOEL for parental toxicity was 10 ppm (0.7 and 
0.9 mg/kg/day for males and females, respectively) based on decreased 
plasma and RBC cholinesterase activities at 250 ppm (17 and 21 mg/kg/
day for males and females, respectively).
    The acceptable developmental studies (prenatal developmental 
toxicity studies in rats and rabbits and 2-generation reproduction 
study in rats) provided no

[[Page 11242]]

indication of increased sensitivity of rats or rabbits to in utero and 
or post-natal exposure to triazamate. Triazamate Technical is not a 
developmental or reproductive toxicant.
    4. Subchronic toxicity. In subacute and subchronic dietary toxicity 
studies, Triazamate Technical produced no evidence of adverse effects 
other than those associated with cholinesterase inhibition:
    i. In a 90-day dietary toxicity study with Triazamate Technical in 
the rat, the NOEL for blood cholinesterase inhibition was 50 ppm (3.2 
and 3.9 mg/kg/day for males and females, respectively), based on 
decreases in plasma and RBC cholinesterase activities at 500 ppm (32 
and 39 mg/kg/day for males and females, respectively). The NOEL for 
brain cholinesterase inhibition and/or clinical signs was 500 ppm (32 
and 39 mg/kg/day for males and females respectively) based on decreased 
brain cholinesterase activity and decreased body weight gain and feed 
consumption at 1,500 ppm (93 and 117 mg/kg/day for males and females, 
respectively).
    ii. In a guideline subchronic neurotoxicity study (90-day dietary 
feeding) with Triazamate Technical in the rat, the NOEL for blood 
cholinesterase inhibition was 10 ppm (0.6 and 0.7 mg/kg/day for males 
and females, respectively), based on reductions in plasma and RBC 
cholinesterase activities at 250 ppm (14.3 and 17.1 mg/kg/day for males 
and females, respectively). The NOEL for brain cholinesterase 
inhibition and/or clinical signs was 250 ppm (14.3 and 17.1 mg/kg/day 
for males and females respectively) based on decreases in brain 
cholinesterase activity and cholinergic signs at 1,500 ppm (87 and 104 
mg/kg/day for males and females, respectively).
    iii. In a 90-day dietary toxicity study with Triazamate Technical 
in the mouse, the NOEL for blood cholinesterase inhibition was 2 ppm 
(0.4 and 0.5 mg/kg/day for males and females, respectively) based on 
decreases in plasma cholinesterase activity at 25 ppm (4 and 6 mg/kg/
day for males and females, respectively). The NOEL for brain 
cholinesterase and/or clinical signs was 250 ppm (46 and 67 mg/kg/day 
for males and females, respectively) based on decreases brain 
cholinesterase and decreases body weight and feed consumption at 1,000 
ppm (164 and 222 mg/kg/day for males and females, respectively).
    iv. In a 90-day dietary toxicity study with Triazamate Technical in 
the dog, the NOEL for blood cholinesterase inhibition was 1 ppm for 
males only (0.03 mg/kg/day) based on decreases in plasma cholinesterase 
at 10 ppm (0.3 mg/kg/day). The dose of 1 ppm was a lowest-observed-
effect-level (LOEL) for females based on the presence of decreased 
plasma cholinesterase activity (24%). The NOEL for clinical signs was 
10 ppm (0.3 mg/kg/day for males and females) based a few clinical signs 
at 100 ppm (3.1 mg/kg/day for males and females).
    v. In a 21-day dermal toxicity study with Triazamate Technical, the 
NOEL blood and brain cholinesterase inhibition was 10 mg/kg based on 
decreases plasma, RBC and brain cholinesterase activities at 100 mg/kg.
    5. Chronic toxicity-- i. Rat, mouse, and dog studies. In chronic 
dietary toxicity studies, Triazamate Technical produced no evidence of 
adverse effects other than those associated with cholinesterase 
inhibition and was not oncogenic in the rat and mouse.
    In a combined chronic dietary toxicity/oncogenicity study (24 
months) in rats with Triazamate Technical, no evidence of oncogenicity 
was observed at doses up to 1,250 ppm (62.5 mg/kg/day for males and 
females; HDT). The NOEL for blood cholinesterase inhibition was 10 ppm 
(0.5 and 0.6 mg/kg/day for males and females, respectively) based on 
decreases in plasma and RBC cholinesterase activity at 250 ppm (11.5 
and 14.5 mg/kg/day in males and females, respectively). The NOEL for 
brain cholinesterase inhibition and/or clinical signs was 250 ppm (11.5 
and 14.5 mg/kg/day in males and females, respectively) based on 
clinical signs and decreases in brain cholinesterase inhibition at 
1,250 ppm (62.5 mg/kg/day for males and females).
    In a combined chronic dietary toxicity study (18 months) in mice 
with Triazamate Technical, no evidence of oncogenicity was observed at 
doses up to 1,000-1,500 ppm (130-195 mg/kg/day for males and females; 
HDT). The NOEL for blood cholinesterase inhibition was 1 ppm (0.1 and 
0.2 mg/kg/day for males and females, respectively) based on decreased 
plasma cholinesterase activity at 50 ppm (6.7 and 8.4 mg/kg/day for 
males and females, respectively). The NOEL for brain cholinesterase 
inhibition and/or clinical signs was 50 ppm (6.7 and 8.4 mg/kg/day for 
males and females, respectively) based on decreased brain 
cholinesterase activity and other evidence of systemic toxicity at 
1,000-1,500 ppm (130-195 mg/kg/day for males and females).
    In a chronic dietary toxicity study (12 months) in dogs with 
Triazamate Technical, the NOEL for blood cholinesterase inhibition was 
0.9 ppm (0.023 and 0.025 mg/kg/day for males and females, respectively) 
based on decreased plasma cholinesterase activity at 15.0 ppm (0.42 mg/
kg/day for both males and females). The NOEL for brain cholinesterase 
inhibition was 15.0 ppm (0.42 mg/kg/day for both males and females) 
based on decreased brain cholinesterase activity at 150 ppm (4.4 and 
4.7 mg/kg/day for males and females, respectively).
    ii. Human studies. A randomized double blind ascending dose study 
was conducted in human male volunteers to determine the safety and 
tolerability of Triazamate Technical and to establish a NOEL for 
adverse clinical toxicity. Single doses of Triazamate Technical, when 
administered orally by capsule to healthy male subjects, were tolerated 
up to and including a dose of 1.0 mg/kg. The 3.0 mg/kg dose of 
triazamate was not clinically tolerated well. Clinically, the NOEL was 
0.3 mg/kg of triazamate based on minimal clinical signs at 1.0 mg/kg 
that were considered possibly related to treatment. Transient decreases 
in plasma and RBC cholinesterase occurred at doses lower than the dose 
that elicited adverse clinical signs.
    Using its Guidelines for Carcinogen Risk Assessment published 
September 24, 1986 (51 FR 33992), Rohm and Haas Company considers 
triazamate to be classified as a Group ``E,'' not a likely human 
carcinogen.
    A Reference dose (RfD) of 0.01 mg/kg/day is proposed for humans, 
based on the clinical NOEL in the human study (0.3 mg/kg) and dividing 
by a safety factor of 30. The dose of 0.3 mg/kg was the highest dose in 
humans that did not produce toxicologically significant adverse effects 
(i.e., signs of cholinergic toxicity) and is 10 times lower than a dose 
that produced unequivocal signs of cholinergic toxicity in man. In 
addition, the clinical NOEL in humans is comparable to the no-
observable-adverse-effect level (NOAEL) of 0.42 mg/kg/day following 
chronic dosing in the dog, the most sensitive laboratory animal 
species. A safety factor of 10 is applied to the clinical NOEL in 
humans to account for potential variability within humans with respect 
to sensitivity towards triazamate. An additional, safety factor of 3 is 
included, since at 0.03 mg/kg (i.e., 1/10th the dose that 
was a clinical NOEL) there was a transient but measurable depression in 
plasma cholinesterase in humans. Although a change in the plasma 
pseudo-cholinesterase (i.e., butyl-cholinesterase) is not 
toxicologically significant since this enzyme is not molecularly 
similar to acetyl-cholinesterase, the additional uncertainty factor of 
3 establishes a RfD at a level where one would predict no

[[Page 11243]]

measurable response of any kind, irrespective of the toxicological 
significance of the finding.
    6. Animal metabolism. The adsorption, distribution, excretion and 
metabolism of triazamate in rats, dogs and goats was investigated. 
Triazamate is rapidly absorbed when given orally (capsule or gavage) 
but slower following dietary intake. Peak blood levels following 
dietary administration were 10-fold lower than after gavage 
administration of an equivalent mg/kg/dose. Elimination is 
predominately by urinary excretion and triazamate does not accumulate 
in tissues. The metabolism of triazamate proceeds via ester hydrolysis 
and then a rapid stepwise cleavage of the carbamoyl group. The free 
acid, (RH-0422) is the only toxicologically significant metabolite, 
given that it contains the carbamoyl group. Other metabolites of 
triazamate, which are seen in other animal and plant metabolism 
studies, do not contain the carbamoyl group and do not produce 
cholinesterase inhibition.
    7. Metabolite toxicology. Common metabolic pathways for triazamate 
have been identified in both plants (apple) and animals (rat, goat, 
hen). The metabolic pathway common to both plants and animals involves 
oxidative demethylation of the carbamoyl group. Extensive degradation 
and elimination of polar metabolites occurs in animals such that 
residue are unlikely to accumulate in humans or animals exposed to 
these residues through the diet.
    8. Endocrine disruption. The toxicology profile of triazamate shows 
no evidence of physiological effects characteristic of the disruption 
of mammalian hormones. In developmental and reproductive studies there 
was no evidence of developmental or reproductive toxicity. In addition, 
the molecular structure of triazamate does not suggest that this 
compound would disrupt the mammalian hormone system. Overall, the 
weight of evidence provides no indication that triazamate has endocrine 
activity in vertebrates.

C. Aggregate Exposure

    1. Dietary exposure. A RfD of 0.01 mg/kg/day is proposed for 
humans, based on the clinical NOEL in the human study (0.3 mg/kg) and 
dividing by a safety factor of 30.
    2. Food-- i. Acute risk. An acute dietary risk assessment (Dietary 
Exposure Evaluation Model, Novigen Sciences Inc., 1997) was conducted 
for triazamate using two approaches: (a) a Tier 1 approach using a 
tolerance level residue of 0.1 ppm and (b) Monte Carlo simulations 
using an entire distribution of field trial residues for pome fruit and 
adjusted for percent crop treated (Tier 3). Using the Tier 1 approach 
margins of exposure (MOEs) at the 95th and 99th 
percentiles of exposure for the overall U.S. population were 572 and 
199, respectively. Using the Tier 3 procedure in which residues were 
adjusted for percent crop treated, the MOEs for the 95th and 
99th percentiles were 8,769 and 1,511, respectively. Acute 
exposure was also estimated for non-nursing infants, the most sensitive 
sub-population. For this population, MOEs at the 95th and 
99th percentiles of exposure were 113 and 83, respectively. 
Using the Tier 3 method, MOEs were 909 and 396, respectively. Acute 
dietary risk is considered acceptable if the MOE is greater than 30, an 
appropriate safety factor when based on a human clinical study. Even 
under the conservative assumptions presented here, the more realistic 
estimates of dietary exposure (Tier 3 analyses) clearly demonstrate 
adequate MOEs up to the 99th percentile of exposure for all 
population subgroups.
    ii. Chronic risk. Chronic dietary risk assessments (Dietary 
Exposure Evaluation Model, Novigen Sciences Inc., 1997) were conducted 
for triazamate using two approaches: (a) using a tolerance level 
residue of 0.1 ppm assuming 100% of crop is treated and (b) using a 
tolerance level residue of 0.1 ppm adjusted for projected percent crop 
treated. The Theoretical Maximum Residue Contribution (TMRC) from the 
proposed pome fruit tolerance represents 0.91% of the RfD for the U.S. 
population as a whole. The subgroup with the greatest chronic exposure 
is non-nursing infants (less than 1 year old), for which the TMRC 
estimate represents 6.3% of the RfD. The chronic dietary risks from 
this use do not exceed EPA's level of concern.
    3. Drinking water. Both triazamate and its cholinesterase-
inhibiting metabolite RH-0422 are degraded rapidly in soil. This rapid 
degradation has been observed in both laboratory and field studies and 
makes it highly unlikely that measurable residues of either compound 
would be found in ground or surface water when triazamate is applied 
according to the proposed EUP label directions.
    4. Non-dietary exposure. Triazamate is not registered for either 
indoor or outdoor residential use. Non-occupational exposure to the 
general population is therefore not expected and not considered in 
aggregate exposure estimates.

D. Cumulative Effects

    The potential for cumulative effects of triazamate with other 
substances that have a common mechanism of toxicity was considered. It 
is recognized the triazamate, although structurally a pseudo-carbamate, 
exhibits toxicity similar to the carbamate class of insecticides, and 
that these compounds produce a reversible inhibition of the enzyme 
cholinesterase. However, Rohm and Haas Company concludes that 
consideration of a common mechanism of toxicity is not appropriate at 
this time since EPA does not have the methodology to resolve this 
complex scientific issue concerning common mechanisms of toxicity. 
Based on these points, Rohm and Haas Company has considered only the 
potential risks of triazamate and RH-0422 in its cumulative exposure 
assessment.

E. Safety Determination

    1. U.S. population. The acute and chronic dietary exposure to 
triazamate and its metabolite from the proposed use on pome fruit were 
evaluated. Exposure to triazamate and its toxicologically significant 
metabolite on pome fruit does not pose an unreasonable health risk to 
consumers including the sensitive subgroup non-nursing infants. In Tier 
1 and Tier 3 acute analyses for the 95th percentile 
exposures, MOEs were greater than 100 for the general U.S. population. 
Using the TMRC and assuming 100% of crop treated, the most conservative 
chronic approach, chronic dietary exposures represents 0.6% of the RfD 
for the U.S. population. EPA generally has no concern for exposures 
below 100% of the RfD because the RfD represents the level at or below 
which daily aggregate dietary exposure over a lifetime will not pose 
appreciable risks to human health.
    Using the two conservative exposure assessments described above and 
taking into account the completeness and reliability of the toxicity 
data, Rohm and Haas Company concludes that there is a reasonable 
certainty that no harm will result from aggregate exposure to residues 
of triazamate and its toxicologically significant metabolite to the 
U.S. population.
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of triazamate, data 
from developmental toxicity studies in the rat and rabbit and 2-
generation reproduction studies in the rat are considered. The 
developmental toxicity studies are designed to evaluate adverse effects 
on the developing organism resulting from pesticide exposure during 
prenatal development

[[Page 11244]]

to one or both parents. Reproduction studies provide information 
relating to effects from exposure to the pesticide on the reproductive 
capability of mating animals and data on systemic toxicity.
    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 effects and the completeness of the 
toxicity database. Based on current toxicological data requirements, 
the toxicology database for triazamate relative to pre- and post- natal 
effects is complete. For triazamate, developmental toxicity was not 
observed in developmental studies using rats and rabbits. The NOEL for 
developmental effects in rats was 64 mg/kg/day and rabbits was 10 mg/
kg/day. In the 2-generation reproductive toxicity study in the rat, the 
reproductive/ developmental toxicity NOEL was 101-132 mg/kg/day. These 
NOELs are 10-fold or higher than those observed for systemic toxicity, 
i.e., cholinesterase inhibition.
    In Tier 1 and Tier 3 acute dietary analyses for the 95th 
percentile exposures, MOEs were greater than 100 for non-nursing 
infants. Using the TMRC and assuming 100% of crop treated, the most 
conservative chronic approach, chronic dietary exposures represents 
6.3% of the RfD for non-nursing infants under 1 year old. Therefore 
Rohm and Haas Company concludes that there is a reasonable certainty 
that no harm will result from aggregate exposure to residues of 
triazamate and its toxicologically significant metabolite to infants 
and children.

F. International Tolerances

    There are no approved CODEX maximum residue levels (MRLs) 
established for residues of triazamate. MRLs have been established for 
apples at 0.1 ppm in the Czech Republic, at 0.02 ppm in Hungary, and at 
0.2 ppm in Korea.

2. Rohm and Haas Company

PP 6E4679

    EPA has received a pesticide petition (PP 6E4679) from Rohm and 
Haas Company, 100 Independence Mall West, Philadelphia, PA 19106. 
proposing pursuant to section 408(d) of the Federal Food, Drug and 
Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR part 180 by 
establishing a tolerance for residues of tebufenozide [benzoic 
acid,3,5-dimethyl-, 1-(1,1-dimethylethyl)-2-(4-ethylbenzoyl) hydrazide] 
in or on the raw agricultural commodity wine grapes at 0.5 ppm. EPA has 
determined that the petition contains data or information regarding the 
elements set forth in section 408(d)(2) of the FFDCA; however, EPA has 
not fully evaluated the sufficiency of the submitted data at this time 
or whether the data supports granting of the petition. Additional data 
may be needed before EPA rules on the petition.

A. Residue Chemistry

    1. Plant metabolism. The metabolism of tebufenozide in plants 
(grapes, apples, rice and sugar beets) is adequately understood for the 
purposes of these tolerances. The metabolism of tebufenozide in all 
crops was similar and involves oxidation of the alkyl substituents of 
the aromatic rings primarily at the benzylic positions. The extent of 
metabolism and degree of oxidation are a function of time from 
application to harvest. In all crops, parent compound comprised the 
majority of the total dosage. None of the metabolites were in excess of 
10% of the total dosage. The metabolism of tebufenozide in goats and 
hens proceeds along the same metabolic pathway as observed in plants. 
No accumulation of residues in tissues, milk or eggs occurred. Because 
wine grape processed fractions are not fed to livestock, there is no 
reasonable expectation that measurable residues of tebufenozide will 
occur in meat, milk, eggs, or poultry.
    2. Analytical method. A high performance liquid chromatographic 
(HPLC) analytical method using ultraviolet (UV) detection has been 
validated for grapes and wine. For these matrices, the method involves 
extraction by blending with solvents, purification of the extracts by 
liquid-liquid partitions and final purification of the residues using 
solid phase extraction column chromatography. The limit of quantitation 
of the method is 0.01 ppm for grapes and 0.005 ppm for wine.

B. Toxicological Profile

    1. Acute toxicity. Tebufenozide has low acute toxicity. 
Tebufenozide Technical was practically non-toxic by ingestion of a 
single oral dose in rats and mice (LD50 > 5,000 mg/kg) and 
was practically non-toxic by dermal application (LD50 > 
5,000 mg/kg). Tebufenozide Technical was not significantly toxic to 
rats after a 4-hour inhalation exposure with an LC50 value 
of 4.5 mg/L (highest attainable concentration), is not considered to be 
a primary eye irritant or a skin irritant and is not a dermal 
sensitizer. An acute neurotoxicity study in rats did not produce any 
neurotoxic or neuropathologic effects.
    2. Genotoxicity. Tebufenozide technical was negative (non-
mutagenic) in an Ames assay with and without hepatic enzyme activation 
and in a reverse mutation assay with E. coli. Tebufenozide technical 
was negative in a hypoxanthine guanine phophoribosyl transferase 
(HGPRT) gene mutation assay using Chinese hamster ovary (CHO) cells in 
culture when tested with and without hepatic enzyme activation. In 
isolated rat hepatocytes, tebufenozide technical did not induce 
unscheduled DNA synthesis (UDS) or repair when tested up to the maximum 
soluble concentration in culture medium. Tebufenozide did not produce 
chromosome effects in vivo using rat bone marrow cells or in vitro 
using Chinese hamster ovary cells (CHO). On the basis of the results 
from this battery of tests, it is concluded that tebufenozide is not 
mutagenic or genotoxic.
    3. Reproductive and developmental toxicity. NOELs for developmental 
and maternal toxicity to tebufenozide were established at 1,000 mg/kg/
day (HDT) in both the rat and rabbit. No signs of developmental 
toxicity were exhibited.
    In a 2-generation reproduction study in the rat, the reproductive/
developmental toxicity NOEL of 12.1 mg/kg/day was 14-fold higher than 
the parental (systemic) toxicity NOEL 10 ppm 0.85 mg/kg/day. Equivocal 
reproductive effects were observed only at the 2,000 ppm dose.
    In a second rat reproduction study, the equivocal reproductive 
effects were not observed at 2,000 ppm (the NOEL equal to 149-195 mg/
kg/day) and the NOEL for systemic toxicity was determined to be 25 ppm 
(1.9-2.3 mg/kg/day).
    4. Subchronic toxicity. The NOEL in a 90-day rat feeding study was 
200 ppm (13 mg/kg/day for males, 16 mg/kg/day for females). The LOEL 
was 2,000 ppm (133 mg/kg/day for males, 155 mg/kg/day for females). 
Decreased body weights in males and females was observed at the LOEL of 
2,000 ppm. As part of this study, the potential for tebufenozide to 
produce subchronic neurotoxicity was investigated. Tebufenozide did not 
produce neurotoxic or neuropathologic effects when administered in the 
diets of rats for 3 months at concentrations up to and including the 
limit dose of 20,000 ppm (NOEL = 1,330 mg/kg/day for males, 1,650 mg/
kg/day for females).
    In a 90-day feeding study with mice, the NOEL was 20 ppm (3.4 and 
4.0 mg/kg/day for males and females, respectively). The LOEL was 200 
ppm

[[Page 11245]]

(35.3 and 44.7 mg/kg/day for males and females, respectively). 
Decreases in body weight gain were noted in male mice at the LOEL of 
200 ppm.
    A 90-day dog feeding study gave a NOEL of 50 ppm (2.1 mg/kg/day for 
males and females). The LOEL was 500 ppm (20.1 and 21.4 mg/kg/day for 
males and females, respectively). At the LOEL, females exhibited a 
decrease in rate of weight gain and males presented an increased 
reticulocyte.
    A 10-week study was conducted in the dog to examine the 
reversibility of the effects on hematological parameters that were 
observed in other dietary studies with the dog. Tebufenozide was 
administered for 6-weeks in the diet to 4 male dogs at concentrations 
of either 0 or 1,500 ppm. After the 6 weeks, the dogs receiving treated 
feed were switched to the control diet for 4- weeks. Hematological 
parameters were measured in both groups prior to treatment, at the end 
of the 6-week treatment, after 2-weeks of recovery on the control diet 
and after 4-weeks of recovery on the control diet. All hematological 
parameters in the treated/recovery group were returned to control 
levels indicating that the effects of tebufenozide on the hemopoietic 
system are reversible in the dog.
    In a 28-day dermal toxicity study in the rat, the NOEL was 1,000 
mg/kg/day, the highest dose tested. Tebufenozide did not produce 
toxicity in the rat when administered dermally for 4-weeks at doses up 
to and including the limit dose of 1,000 mg/kg/day.
    5. Chronic toxicity. A 1-year feeding study in dogs resulted in 
decreased red blood cells, hematocrit, and hemoglobin and increased 
Heinz bodies, reticulocytes, and platelets at the LOEL of 8.7 mg/kg/
day. The NOEL in this study was 1.8 mg/kg/day.
    An 18-month mouse carcinogenicity study showed no signs of 
carcinogenicity at dosage levels up to and including 1,000 ppm, the 
highest dose tested.
    In a combined rat chronic/oncogenicity study, the NOEL for chronic 
toxicity was 100 ppm (4.8 and 6.1 mg/kg/day for males and females, 
respectively) and the LOEL was 1,000 ppm (48 and 61 mg/kg/day for males 
and females, respectively). No carcinogenicity was observed at the 
dosage levels up to 2,000 ppm (97 mg/kg/day and 125 mg/kg/day for males 
and females, respectively).
    6. Animal metabolism. The adsorption, distribution, excretion and 
metabolism of tebufenozide in rats was investigated. Tebufenozide is 
partially absorbed, is rapidly excreted and does not accumulate in 
tissues. Although tebufenozide is mainly excreted unchanged, a number 
of polar metabolites were identified. These metabolites are products of 
oxidation of the benzylic ethyl or methyl side chains of the molecule. 
These metabolites were detected in plant and other animal (rat, goat, 
hen) metabolism studies.
    7. Metabolite toxicology. Common metabolic pathways for 
tebufenozide have been identified in both plants (grape, apple, rice 
and sugar beet) and animals (rat, goat, hen). The metabolic pathway 
common to both plants and animals involves oxidation of the alkyl 
substituents (ethyl and methyl groups) of the aromatic rings primarily 
at the benzylic positions. Extensive degradation and elimination of 
polar metabolites occurs in animals such that residue are unlikely to 
accumulate in humans or animals exposed to these residues through the 
diet.
    8. Endocrine disruption. The toxicology profile of tebufenozide 
shows no evidence of physiological effects characteristic of the 
disruption of the hormone estrogen. Based on structure-activity 
information, tebufenozide is unlikely to exhibit estrogenic activity. 
Tebufenozide was not active in a direct in vitro estrogen binding 
assay. No indicators of estrogenic or other endocrine effects were 
observed in mammalian chronic studies or in mammalian and avian 
reproduction studies. Ecdysone has no known effects in vertebrates. 
Overall, the weight of evidence provides no indication that 
tebufenozide has endocrine activity in vertebrates.

C. Aggregate Exposure

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

[[Page 11246]]

perform quantitative risk assessments have demonstrated that drinking 
water exposure is typically a small percentage of the total exposure 
when compared to the total dietary exposure. This observation holds 
even for pesticides detected in wells and drinking water at levels 
nearing or exceeding established MCLs. Considering the precautionary 
language on the label and based on our knowledge of previous experience 
with persistent chemicals, significant exposure from residues of 
tebufenozide in drinking water is not anticipated.
    4. Non-dietary exposure. Tebufenozide is not registered for either 
indoor or outdoor residential use. Non-occupational exposure to the 
general population is therefore not expected and not considered in 
aggregate exposure estimates.

D. Cumulative Effects

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

E. Safety Determination

    1. U.S. population. Using the conservative exposure assumptions 
described above and taking into account the completeness and 
reliability of the toxicity data, the dietary exposure to tebufenozide 
from the current and future tolerances will utilize 20.1% of the RfD 
for the U.S. population and 52.0% for non-nursing infants under 1-year 
old. Using anticipate residue levels for these crops utilizes 3.38% of 
the RfD for the U.S. population and 12.0% for non-nursing infants. EPA 
generally has no concern for exposures below 100% of the RfD because 
the RfD represents the level at or below which daily aggregate dietary 
exposure over a lifetime will not pose appreciable risks to human 
health. Rohm and Haas concludes that there is a reasonable certainty 
that no harm will result from aggregate exposure to tebufenozide 
residues to the U.S. population and non-nursing infants.
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of tebufenozide, data 
from developmental toxicity studies in the rat and rabbit and 2-
generation reproduction studies in the rat are considered. The 
developmental toxicity studies are designed to evaluate adverse effects 
on the developing organism resulting from pesticide exposure during 
prenatal development to one or both parents. Reproduction studies 
provide information relating to effects from exposure to the pesticide 
on the reproductive capability of mating animals and data on systemic 
toxicity. Developmental toxicity was not observed in developmental 
studies using rats and rabbits. The NOEL for developmental effects in 
both rats and rabbits was 1,000 mg/kg/day, which is the limit dose for 
testing in developmental studies.
    In the 2-generation reproductive toxicity study in the rat, the 
reproductive/developmental toxicity NOEL of 12.1 mg/kg/day was 14-fold 
higher than the parental (systemic) toxicity NOEL (0.85 mg/kg/day). The 
reproductive (pup) LOEL of 171.1 mg/kg/day was based on a slight 
increase in both generations in the number of pregnant females that 
either did not deliver or had difficulty and had to be sacrificed. In 
addition, the length of gestation increased and implantation sites 
decreased significantly in F1 dams. These effects were not replicated 
at the same dose in a second 2-generation rat reproduction study. In 
this second study, reproductive effects were not observed at 2,000 ppm 
(the NOEL equal to 149-195 mg/kg/day) and the NOEL for systemic 
toxicity was determined to be 25 ppm (1.9-2.3 mg/kg/day).
    Because these reproductive effects occurred in the presence of 
parental (systemic) toxicity and were not replicated at the same doses 
in a second study, these data do not indicate an increased pre-natal or 
post-natal sensitivity to children and infants (that infants and 
children might be more sensitive than adults) to tebufenozide exposure. 
FFDCA section 408 provides that EPA shall apply an additional safety 
factor for infants and children in the case of threshold effects to 
account for pre- and post-natal toxicity and the completeness of the 
data base unless EPA concludes that a different margin of safety is 
appropriate. Based on current toxicological data discussed above, an 
additional uncertainty factor is not warranted and the RfD at 0.018 mg/
kg/day is appropriate for assessing aggregate risk to infants and 
children. Rohm and Haas concludes that there is a reasonable certainty 
that no harm will occur to infants and children from aggregate exposure 
to residues of tebufenozide.

F. International Tolerances

    There are no approved CODEX maximum residue levels (MRLs) 
established for residues of tebufenozide. At the 1996 Joint Meeting for 
Pesticide Residues, the FAO expert panel considered residue data for 
grapes and proposed an MRL (Step 3) of 0.5 mg/kg.

3. Valent U.S.A. Corporation

PP 6F4737

    EPA has received a pesticide petition (PP 6F4737) from Valent 
U.S.A. Corporation, 1333 N. California Blvd., Walnut Creek, CA 94596 
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 pyriproxyfen, 2-[ 1-methyl-2-
(4-phenoxyphenoxy) ethoxy) ethoxy] pyridine in or on the raw 
agricultural commodity cottonseed at 0.05 ppm and cotton gin byproducts 
at 2.0 ppm. EPA has determined that the petition contains data or 
information regarding

[[Page 11247]]

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--Nature of the residues in food, feed and 
secondary residues. The residue of concern is best defined as the 
parent, pyriproxyfen.
    The nature of the residues in cotton, apples, and animals is 
adequately understood. Metabolism of 14C-pyriproxyfen 
labelled in the phenoxyphenyl ring and in the pyridyl ring was studied 
in cotton, apples, lactating goats, and laying hens (and rats). The 
nature of the residue is defined by the metabolism studies primarily as 
pyriproxyfen. The major metabolic pathways in plants is hydroxylation 
and cleavage of the ether linkage, followed by further metabolism into 
more polar products by oxidation or conjugation reactions, however, the 
bulk of the radiochemical residue was parent. Comparing metabolites 
from cotton, apple, goat and hen (and rat) shows that there are no 
significant metabolites in plants which are not also present in the 
excreta or tissues of animals.
    Ruminant and poultry metabolism studies demonstrated that transfer 
of administered 14C residues to tissues was low. Total 
14C residues in goat milk, muscle and tissues accounted for 
less than 2% of the administered dose, and were less than 1 ppm in all 
cases. In poultry, total 14C residues in eggs, muscle and 
tissues accounted for about 2.7% of the administered dose, and were 
less than 1 ppm in all cases except for gizzard.
    2. Analytical method-- Pyriproxyfen and metabolites. Practical 
analytical methods for detecting and measuring levels of pyriproxyfen 
(and relevant metabolites) have been developed and validated in cotton 
raw agricultural commodities, respective processing fractions, animal 
tissues, and environmental samples. The methods have been independently 
validated in cottonseed, apples, soil, and oranges and the extraction 
methodology has been validated using aged radiochemical residue samples 
from metabolism studies. EPA has successfully validated the analytical 
method for analysis of cottonseed raw agricultural commodity (personal 
communication). The limit of detection of pyriproxyfen in the methods 
is 0.01 ppm which will allow monitoring of food with residues at or 
above the levels proposed for the tolerances.
    3. Magnitude of residues-- i. Cotton. Data from fifteen field 
trials in cotton conducted in 1994 and 1995, showed that mean 
pyriproxyfen residues from duplicate samples were <0.01 - 0.04 ppm in 
cottonseed, and 0.35 - 2.3 ppm in gin trash, following two or three 
treatments totaling 80 grams active ingredient per acre at 14 day 
intervals with a 28 day pre-harvest interval. The seasonal use rate 
tested in the residue trials was approximately 2.6 times the maximum 
seasonal use rate presently proposed for cotton in the pending 
KNACK Insect Growth Regulator label. No concentration of 
residues was observed from processing cottonseed treated with an 12.8 x 
application rate into hulls, meal, crude oil or refined oil.
    ii. Secondary residues. Since low residues were detected in cotton 
derived animal feed items and since animal metabolism studies do not 
show potential for significant residue transfer, detectable secondary 
residues in animal tissues, milk, and eggs are not expected. Therefore, 
tolerances are not needed for these commodities.
    iii. Rotational crops. The results of a confined rotational crops 
accumulation study indicate that no rotational crop planting 
restrictions or rotational crop tolerances are required.

B. Toxicological Profile

    1. Acute toxicity. The acute toxicity of technical grade 
pyriproxyfen is low by all routes. The compound is classified as 
Category III for acute dermal and inhalation toxicity, and Category IV 
for acute oral toxicity, and skin/eye irritation. Pyriproxyfen is not a 
skin sensitizing agent.
    2. Genotoxicity. Pyriproxyfen does not present a genetic hazard. 
Pyriproxyfen was negative in the following tests for mutagenicity: Ames 
assay with and without S9, in vitro unscheduled DNA synthesis in HeLa 
S3 cells, in vitro gene mutation in V79 Chinese hamster cells, and in 
vitro chromosomal aberration with and without S9 in Chinese hamster 
ovary cells.
    3. Reproductive and developmental toxicity. Pyriproxyfen is not a 
developmental or reproductive toxicant. Developmental toxicity studies 
have been performed in rats and rabbits, and multigenerational effects 
on reproduction were tested in rats. These studies have been reviewed 
and found to be acceptable to the Agency.
    In the developmental toxicity study conducted with rats, technical 
pyriproxyfen was administered by gavage at levels of 0, 100, 300, and 
1,000 mg/kg bw/day during gestation days 7-17. Maternal toxicity 
(mortality, decreased body weight gain and food consumption, and 
clinical signs of toxicity) was observed at doses of 300 mg/kg body 
weight/day (bw/day) and greater. The maternal NOEL was 100 mg/kg bw/
day. A transient increase in skeletal variations was observed in rat 
fetuses from females exposed to 300 mg/kg bw/day and greater. These 
effects were not present in animals examined at the end of the 
postnatal period, therefore, the NOEL for prenatal developmental 
toxicity was 100 mg/kg bw/day. An increased incidence of visceral and 
skeletal variations was observed postnatally at 1,000 mg/kg bw/day. The 
NOEL for postnatal developmental toxicity was 300 mg/kg bw/day.
    In the developmental toxicity study conducted with rabbits, 
technical pyriproxyfen was administered by gavage at levels of 0, 100, 
300, and 1,000 mg/kg bw/day during gestation days 6-18. Maternal 
toxicity (clinical signs of toxicity including one death, decreased 
body weight gain and food consumption, and abortions or premature 
deliveries) was observed at oral doses of 300 mg/kg bw/day or higher. 
The maternal NOEL was 100 mg/kg bw/day. No developmental effects were 
observed in the rabbit fetuses. The NOEL for developmental toxicity in 
rabbits was 1,000 mg/kg bw/day.
    In the rat reproduction study, pyriproxyfen was administered in the 
diet at levels of 0, 200, 1,000, and 5,000 ppm through two generations 
of rats. Adult systemic toxicity (reduced body weights, liver and 
kidney histopathology, and increased liver weight) was produced at the 
5,000 ppm dose (453 mg/kg bw/day in males, 498 mg/kg bw/day in females 
during the pre-mating period). The systemic NOEL was 1,000 ppm (87 mg/
kg bw/day in males, 96 mg/kg bw/day in females). No effects on 
reproduction were produced at 5,000 ppm, the HDT.
    4. Subchronic toxicity. Subchronic oral toxicity studies conducted 
with pyriproxyfen technical in the rat, mouse and dog indicate a low 
level of toxicity. Effects observed at high dose levels consisted 
primarily of decreased body weight gain; increased liver weights; 
histopathological changes in the liver and kidney; decreased red blood 
cell counts, hemoglobin and hematocrit; altered blood chemistry 
parameters; and, at 5,000 and 10,000 ppm in mice, a decrease in 
survival rates. The NOELs from these studies were 400 ppm (23.5 mg/kg 
bw/day for males, 27.7 mg/kg bw/day for females) in rats, 1,000 ppm 
(149.4 mg/kg bw/day for males, 196.5

[[Page 11248]]

mg/kg bw/day for females) in mice, and 100 mg/kg bw/day in dogs.
    In a four week inhalation study of pyriproxyfen technical in rats, 
decreased body weight and increased water consumption were observed at 
1,000 mg/m3. The NOEL in this study was 482 mg/
m3.
    A 21-day dermal toxicity study in rats with pyriproxyfen technical 
did not produce any signs of dermal or systemic toxicity at 1,000 mg/kg 
bw/day, the highest dose tested. In a 21-day dermal study conducted 
with KNACK Insect Growth Regulator the test material produced 
a NOEL of 1,000 mg/kg bw/day (HDT) for systemic effects, and a NOEL for 
skin irritation of 100 mg/kg bw/day.
    5. Chronic toxicity. Pyriproxyfen technical has been tested in 
chronic studies with dogs, rats and mice. EPA has established a RfD for 
pyriproxyfen of 0.35 mg/kg bw/day, based on the NOEL in female rats 
from the two year chronic/oncogenicity study. Effects cited by EPA in 
the Reference Dose Tracking Report include negative trend in mean red 
blood cell volume, increased hepatocyte cytoplasm and cytoplasm:nucleus 
ratios, and decreased sinusoidal spaces.
    Pyriproxyfen is not a carcinogen. Studies with pyriproxyfen have 
shown that repeated high dose exposures produced changes in the liver, 
kidney and red blood cells, but did not produce cancer in test animals. 
No oncogenic response was observed in a rat two-year chronic feeding/
oncogenicity study or in a seventy-eight week study on mice . The 
oncogenicity classification of pyriproxyfen is ``E'' (no evidence of 
carcinogenicity for humans).
    Pyriproxyfen technical was administered to dogs in capsules at 
doses of 0, 30, 100, 300 and 1,000 mg/kg bw/day for one year. Dogs 
exposed to dose levels of 300 mg/kg bw/day or higher showed overt 
clinical signs of toxicity, elevated levels of blood enzymes and liver 
damage. The NOEL in this study was 100 mg/kg bw/day.
    Pyriproxyfen technical was administered to mice at doses of 0, 120, 
600 and 3,000 ppm in diet for 78 weeks. The NOEL for systemic effects 
in this study was 600 ppm (84 mg/kg bw/day in males, 109.5 mg/kg bw/day 
in females), and a LOEL of 3,000 ppm (420 mg/kg bw/day in males, 547 
mg/kg bw/day in females) was established based on an increase in kidney 
lesions.
    In a two-year study in rats, pyriproxyfen technical was 
administered in the diet at levels of 0, 120, 600, and 3,000 ppm. The 
NOEL for systemic effects in this study was 600 ppm (27.31 mg/kg bw/day 
in males, 35.1 mg/kg bw/day in females). A LOEL of 3,000 ppm (138 mg/kg 
bw/day in males, 182.7 mg/kg bw/day in females) was established based 
on a depression in body weight gain in females.
    6. Animal metabolism. The mammalian metabolism of pyriproxyfen is 
understood. The absorption, tissue distribution, metabolism and 
excretion of 14C-labeled pyriproxyfen were studied in rats 
after single oral doses of 2 or 1,000 mg/kg bw (phenoxyphenyl and 
pyridyl label), and after a single oral dose of 2 mg/kg bw 
(phenoxyphenyl label only) following 14 daily oral doses at 2 mg/kg bw 
of unlabelled material. For all dose groups, most (88-96%) of the 
administered radiolabel was excreted in the urine and feces within 2 
days after radiolabeled test material dosing, and 92-98% of the 
administered dose was excreted within 7 days. Seven days after dosing, 
tissue residues were generally low, accounting for no more than 0.3% of 
the dosed 14C. Radiocarbon concentrations in fat were the 
higher than in other tissues analyzed. Recovery in tissues over time 
indicates that the potential for bioaccumulation is minimal. There were 
no significant sex or dose-related differences in excretion or 
metabolism.
    7. Metabolite toxicology. Metabolism studies of pyriproxyfen in 
rats, goats and hens, as well as the fish bioaccumulation study 
demonstrate that the parent is very rapidly metabolized and eliminated. 
In the rat, most (88-96%) of the administered radiolabel was excreted 
in the urine and feces within 2 days of dosing, and 92-98% of the 
administered dose was excreted within 7 days. Seven days after dosing, 
tissue residues were low, accounting for no more than 0.3% of the dosed 
14C. Because parent and metabolites are not retained in the 
body, the potential for acute toxicity from in situ formed metabolites 
is low. The potential for chronic toxicity is adequately tested by 
chronic exposure to the parent at the MTD and consequent chronic 
exposure to the internally formed metabolites.
    Seven metabolites of pyriproxyfen, 4,-OH-pyriproxyfen, 
5-OH-pyriproxyfen, desphenyl-pyriproxyfen, POPA, 
PYPAC, 2-OH-pyridine and 2,5-diOH-pyridine, have been tested for 
mutagenicity (Ames) and acute oral toxicity to mice. All seven 
metabolites were tested in the Ames assay with and without S9 at doses 
up to 5,000 micro-grams per plate or up to the growth inhibitory dose. 
The metabolites did not induce any significant increases in revertant 
colonies in any of the test strains. Positive control chemicals showed 
marked increases in revertant colonies. The acute toxicity to mice of 
4,-OH-pyriproxyfen, 5-OH-pyriproxyfen, 
desphenyl-pyriproxyfen, POPA, and PYPAC did not appear to markedly 
differ from pyriproxyfen, with all metabolites having acute oral 
LD50 values greater than 2,000 mg/kg bw. The two pyridines, 
2-OH-pyridine and 2,5-diOH-pyridine, gave acute oral LD50 
values of 124 (male) and 166 (female) mg/kg bw, and 1,105 (male) and 
1,000 (female) mg/kg bw, respectively.
    8. Endocrine disruption. Pyriproxyfen is specifically designed to 
be an insect growth regulator and is known to produce juvenoid effects 
on arthropod development. However, this mechanism-of-action in target 
insects and other arthropods has no relevance to mammalian endocrine 
systems. While specific tests, uniquely designed to evaluate the 
potential effects of pyriproxyfen on mammalian endocrine systems have 
not been conducted, the toxicology of pyriproxyfen has been extensively 
evaluated in acute, sub-chronic, chronic, developmental, and 
reproductive toxicology studies including detailed histopathology of 
numerous tissues. The results of these studies show no evidence of any 
endocrine-mediated effects and no pathology of the endocrine organs. 
Consequently, it is concluded that Sumilarv does not possess estrogenic 
or endocrine disrupting properties applicable to mammals.

C. Aggregate Exposure

    1. Dietary exposure. EPA has established a RfD for pyriproxyfen of 
0.35 mg/kg bw/day, based on the rat 2 year chronic/oncogenicity study 
and a safety factor of 100. The chronic dietary risk can be evaluated 
using this endpoint. The Agency has not identified acute or short term 
toxicity endpoints of concern for pyriproxyfen. Valent has identified 
the 90-day rat oral toxicity with a NOEL of 23.5 mg/kg bw/day as the 
short term study with the lowest exposure endpoint. This figure will be 
used for all acute and short term risk analyses.
    2. Food. Chronic and acute dietary exposure analyses have been 
performed for pyriproxyfen using (proposed) tolerance level and 
anticipated residues and 100% of the crop treated. Included in the 
analyses are cottonseed, cotton gin trash and secondary residues in 
meat, milk, and eggs. These exposure/risk analyses have been submitted 
to the Agency along with a detailed description of the methodology and 
assumptions used.
    i. Chronic. Long term dietary exposure was calculated for the U.S. 
population and 26 population subgroups. The results from several

[[Page 11249]]

representative subgroups are listed below. The highest exposed sub-
population, Children (1 - 6 Years) with tolerance level exposure, 
showed an occupancy of the RfD of 0.03%. In all other cases, chronic 
dietary exposure was below 0.03 % of the RfD.

       Potential Chronic Dietary Exposure to Pyriproxyfen Residues      
------------------------------------------------------------------------
                                           Exposure (mg/kg bw/day)      
        Population Subgroup        -------------------------------------
                                        Tolerances        Anticipated   
------------------------------------------------------------------------
U.S.population - 48 States - All                                        
 seasons..........................           0.000026           0.000016
U.S. population - Autumn season...           0.000027           0.000017
Midwest Region....................           0.000030           0.000018
All infants.......................           0.000049           0.000030
Non-nursing infants (<1 year old).           0.000065           0.000040
Children (1 - 6 years)............           0.000095           0.000058
Females (13+/pregnant/not nursing)           0.000025           0.000015
------------------------------------------------------------------------

    ii. Acute. A tier 2 acute dietary exposure analysis assuming 100% 
of crop treated was performed for the U.S. population and six subgroups 
-- All Infants, Non-Nursing Infants (<1 Year), Children 1-6, Children 
7-12, Females 13-50, and males 20+. The calculated exposures are all 
very low, ranging from 0.000002 to 0.000018 mg/kg bw/day, for the 
higher exposed proportions, 95 th and 99.9 th 
percentiles, of the subgroups. It should be noted that the population 
sizes are small at the lower probability exposures (e.g. 99 
th and 99.9 th percentiles) oftentimes leading to 
unrealistically high calculated exposures. In all cases, MOEs to 
pyriproxyfen residues exceed one-million.
    3. Drinking water. Since pyriproxyfen is to be applied outdoors to 
growing cotton crops, the potential exists for the parent or its 
metabolites to reach ground or surface water that may be used for 
drinking water.
    i. Ground water. Pyriproxyfen is extremely insoluble in water 
(0.367 mg/L at 25 deg.C), with high octanol/water partitioning 
coefficient (Log P o/w = 5.37 at 25 deg.C), and relatively short soil 
half-life (aerobic soil metabolism T \1/2\ = 6 to 9 days). Given the 
low use rates, the immobility of the parent and the instability of the 
soil metabolites in soil, it is very unlikely that pyriproxyfen or its 
metabolites could leach to and contaminate potable groundwater.
    ii. Surface water. In connection with the potential for dietary 
exposure from surface potable water, a simulation of expected 
environmental concentration (EEC) values in aquatic systems has been 
performed using the Pesticide Root Zone Model (PRZM-2.3) and the 
Exposure Analysis Modeling System, version 2.95 (EXAMSII). The 
simulation was designed to approximate as closely as possible the 
conditions associated with two aerial applications totaling 0.084 lb. 
a.i. per acre to cotton with a 28-day interval. This use pattern 
exceeds the presently proposed use pattern by approximately 1.2 x. The 
results of the modeling estimate that the maximum upper tenth 
percentile concentrations modeled in water adjacent to treated fields 
are instantaneous, 0.23 ppb; 96-hour, 0.14 ppb; and 21 day, 0.08 ppb.
    To obtain a very conservative estimate of a possible dietary 
exposure from drinking water, it could be assumed that all water 
consumed contains pyriproxyfen at the maximum upper tenth percentile 
concentrations modeled in aquatic systems (static, stagnant farm ponds) 
adjacent to treated cotton fields. Standard, conservative exposure 
assumptions of body weight and water consumption (adult 70 kg, 2 kg 
water per day; child 10 kg, 1 kg water) will be used.
    iii Chronic. The 21 day concentration, 0.08 ppb (0.00008 mg/kg), is 
used to represent chronic exposure. The highest possible exposure would 
be 2.3 x 10-6 and 8 x 10-6 mg/kg bw/day for an 
adult and child, respectively. This very small, but probably 
exaggerated, exposure would occupy 0.00065 (adult) and 0.0023 (child) 
percent of the chronic RfD of 0.35 mg/kg bw/day.
    iv. Acute. The modeled instantaneous concentration of 0.23 ppb 
(0.00023 mg/kg), can be used to represent potential acute exposure to 
pyriproxyfen in surface source drinking water. A corresponding 
calculation shows that the maximum acute exposure would be 6.6 x 
10-6 and 2.3 x 10-5 mg/kg bw/day for the adult 
and child, respectively. When compared to the short term endpoint of 
23.5 mg/kg bw/day, MOEs for both adults and children exceed one 
million.
    4. Non-dietary exposure. Pyriproxyfen is the active ingredient in 
numerous registered products for household use -- primarily for indoor, 
non-food applications by consumers. The consumer uses of pyriproxyfen 
typically do not involve chronic exposure. Instead, consumers are 
exposed intermittently to a particular product (e.g., pet care pump 
spray) containing pyriproxyfen. Since pyriproxyfen has a relatively 
short elimination half-life, cumulative toxicological effects resulting 
from bioaccumulation are not plausible following short-term, 
intermittent exposures. Further, pyriproxyfen is short-lived in the 
environment and this indoor domestic use of pyriproxyfen provides only 
relatively short-term reservoirs.
    This non-dietary exposure assessment for pyriproxyfen 
conservatively focuses on upper-bound estimates of potential applicator 
(adult) and post-application (adult and child - less than one year old) 
exposures on the day of application. Subsequent days present no 
applicator exposure, and a decreasing contribution to short-term total 
exposure. The assessment estimates exposures for selected consumer uses 
that are representative, plausible, and reasonable worst case exposure 
scenarios. The scenarios selected include:
    (i) Potential exposures associated with adult application (dermal 
and inhalation exposures) and post-application (adult and child 
inhalation exposures) of pyriproxyfen-containing pet care products; and
    (ii) Potential adult applicator exposures (dermal and inhalation), 
and post-application adult (inhalation) and child (inhalation, dermal, 
incidental oral ingestion associated with hand-to-mouth behavior) 
exposures associated with consumer use of an aerosol carpet spray 
product.
    The risk analyses use a combination of representative models. 
Information from the pesticide handlers exposure data base (PHED) was 
used to estimate exposures to applicators (adult). Surrogate data from 
a study of exposure to indoor broadcast applications were used to 
calculate a series of absorbed dose estimates for adult applicators, 
and

[[Page 11250]]

post-application exposures to adults and children by dermal, 
inhalation, and (hand-to-mouth) oral routes. The methodology, 
assumptions, and estimates are presented in detail in the full FQPA 
exposure analysis, the table below presents the results.

Summary of Estimated Human Application and Post-Application Exposures Associated With Use of Pet Spray and Carpet Spray Products Containing Pyriproxyfen
                                                                as the Active Ingredient                                                                
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                       Daily Dose (mg/kg bw/day)                        
             Product                    Population        Timing of Exposure ---------------------------------------------------------------------------
                                                                                Inhalation\1\        Dermal\2\           Oral\1\             Total      
--------------------------------------------------------------------------------------------------------------------------------------------------------
Pet Spray........................  Adults..............  Application........         4.3 x 10-6              0.085                3NA              0.085
                                                         Post-Application...         1.8 x 10-5                 NA                 NA         1.8 x 10-5
                                                         TOTAL..............         2.2 x 10-5              0.085                 NA              0.085
                                   Children............  Post-Application...         3.7 x 10-5                 NA                 NA         3.7 x 10-5
Carpet Spray.....................  Adults..............  Application........         1.3 x 10-6         5.1 x 10-4                 NA         5.1 x 10-4
                                                         Post-Application...         5.4 x 10-6                 NA                 NA         5.4 x 10-6
                                                         TOTAL..............         6.7 x 10-6         5.1 x 10-4                 NA         5.2 x 10-4
                                   Crawling Infant.....  Post-Application...         1.5 x 10-5         1.3 x 10-3         2.1 x 10-4        1.5 x 10-3 
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ 100 % adsorption.                                                                                                                                   
\2\ Conservatively assumes a dermal absorption factor of 50%.                                                                                           
\3\ Exposure pathway not applicable.                                                                                                                    

    It is important to emphasize that the exposures summarized in the 
table are based on conservative assumptions and surrogate data. 
Further, the exposures are calculated for the day of application. 
Subsequent daily exposures would be less as pyriproxyfen is adsorbed 
into substrate, or dissipates and becomes unavailable by other 
mechanisms. Application exposures on non-application days would be 
zero.
    Further, the Agency has not identified acute or short term toxicity 
endpoints of concern for oral inhalation or dermal exposure. Endpoints 
that could be considered for short term and intermediate exposures 
include developmental toxicity NOEL values of 100 mg/kg bw/day (rat and 
rabbit), rat 21-day dermal systemic NOEL values of 1,000 mg/kg bw/day 
(technical grade and end-use product), a four week rat inhalation 
toxicity NOEL of 482 mg/m3, and, the endpoint chosen by 
Valent to be used in these analyses, the 90-day rat oral toxicity NOEL 
of 23.5 mg/kg bw/day. There are no dermal absorption data for 
pyriproxyfen.
    The largest 1 day exposure is calculated for the applicator of the 
pet spray (0.085 mg/kg bw/day). This value is 57 times larger than the 
next highest calculated exposure which is the total exposure to a 
crawling infant on the day of application of the carpet spray (1.5 x 
10-3 mg/kg bw/day). Furthermore, the return frequency is 
much different. Label instructions allow treatment of the pet every 14-
days during the flea season, while the carpet can be treated only each 
120 days. The 1 day exposure is compared to the smallest short term 
endpoint choosen by Valent, the 90-day rat oral toxicity NOEL of 23.5 
mg/kg bw/day, and a MOE can be calculated. This compares an acute, one 
day, dermal exposure to a sub-chronic 90-day dietary endpoint.
    MOE = Toxicity Endpoint (mg/kg bw/day)  Daily Short Term 
Exposure (mg/kg bw/day)
    MOEPet Spray Applicator, One day  = 276
    Probably more realistic, a short term daily exposure to the adult 
applicator can be calculated and compared to the same endpoint.
    Daily Exposure (mg/kg bw/day) = Applicator Exposure (mg/kg bw/day) 
 Frequency (days)
    MOEPet Spray Applicator = 3,900
    Based on the available toxicity data and the conservative exposure 
assumptions, and because infants and children are not applicators in 
the household, the smallest acute and short term MOE value for children 
is based on post-application exposures. The day of application exposure 
to a crawling infant is the sum of inhalation, dermal adsorption, and 
oral (hand to mouth) exposures. Subsequent daily exposures are not 
quantified, but because of dissipation of the active ingredient in the 
home environment subsequent exposure must be less than exposure on the 
day of application.
    MOECarpet Spray, Crawling Infant = 15,700
    There is usually no cause for concern if MOEs exceed 100. All other 
MOEs that can be calculated from the non-occupational, non-dietary 
exposures summarized in the table above are considerably larger than 
that for the pet spray applicator and (post carpet spray application) 
crawling infant.
    5. Summary of acute and chronic aggregate non-occupational 
exposures. Aggregate exposure is defined as the sum all non-
occupational exposures to the general U.S. population and relevant sub-
populations to the single active ingredient, pyriproxyfen. These 
exposures can be classified as acute, short term, and chronic.
    i. Acute and short term non-occupational exposures. Potential acute 
and short term non-occupational exposures to pyriproxyfen are 
associated with food, water, and household uses -- applicator and post-
application exposures. For preliminary risk analysis, these exposures, 
oftentimes calculated using conservative assumptions and surrogate 
data, are compared to appropriate acute and short term toxicity 
endpoints to yield MOE. Valent has identified the 90-day rat oral 
toxicity with a NOEL of 23.5 mg/kg bw/day as the short term study with 
the lowest exposure endpoint. In general, if exposure estimates are 
conservative and the resulting MOE values are greater than 100, the 
Agency has no cause for concern.
    It is possible to sum calculated acute exposures from various 
sources as shown in the table below. However, summation is exceedingly 
conservative because the approach assumes that two or more low 
probability events occurr symultaneously. For example, it is highly 
unlikely that an individual consuming the 99.9th percentile 
dietary exposure (one-in-a-thousand), also treats a large dog for 
fleas, and consumes all drinking water from a pond surrounded by 
treated cotton fields in a single day. Even so, the short term non-
occupational exposures shown below that sum exposures from food, 
drinking water and household uses of pyriproxyfen gives MOE values all 
much larger than 100. These calculated acute and short term exposures 
are very conservative, and are small enough to be of little 
significance.

[[Page 11251]]



  Aggregate Acute Exposure to Pyriproxyfen for Two Representative U.S.  
                               Populations                              
              (summation of low probability maximum values)             
------------------------------------------------------------------------
                                           Exposure (mg/kg bw/day)      
                                   -------------------------------------
          Exposure Medium                                 Non-Nursing   
                                     U.S. Population   Infant (less than
                                      (all seasons)         1 year)     
------------------------------------------------------------------------
Non-dietary.......................              0.085             0.0015
Food..............................           0.000012           0.000012
Drinking water....................          0.0000066           0.000023
Sum of acute exposures............          0.0850186           0.001535
Margin of exposure................                276             15,300
------------------------------------------------------------------------

    ii. Chronic exposures. Potential chronic exposures to pyriproxyfen 
are considered to be derived from dietary exposures to primary and 
secondary residues in food, and to potential residues in drinking 
water. To calculate the total potential chronic exposure from food and 
drinking water, the calculated exposures from both media can be summed. 
To assess risk these totals can then be compared to the chronic RfD of 
0.35 mg/kg bw/day. If the occupancy of the RfD is less than 100%, the 
Agency usually has little cause for concern. From the table, it can be 
seen that the total potential chronic exposure to pyriproxyfen is truly 
insignificant, and should not be cause for concern.

               Aggregate Chronic Exposure to Pyriproxyfen for Two Representative U.S. Populations               
----------------------------------------------------------------------------------------------------------------
                                                                         Exposure (mg/kg bw/day)                
                                                        --------------------------------------------------------
                    Exposure Medium                                            Non-Nursing                      
                                                          U.S. Population   Infant (less than   Children (1 - 6 
                                                           (all seasons)         1 year)             Years)     
----------------------------------------------------------------------------------------------------------------
Food...................................................           0.000026           0.000065           0.000095
Drinking water.........................................          0.0000023           0.000008           0.000008
Sum of chronic exposures...............................          0.0000283           0.000073           0.000103
Occupancy of RfD (percent).............................             0.0081              0.021              0.029
----------------------------------------------------------------------------------------------------------------

D. Cumulative Effects

    Section 408(b)(2)(D)(v) requires that the Agency must consider 
``available information'' concerning the cumulative effects of a 
particular pesticide's residues and ``other substances that have a 
common mechanism of toxicity''. ``Available information'' in this 
context include not only toxicity, chemistry, and exposure data, but 
also scientific policies and methodologies for understanding common 
mechanisms of toxicity and conducting cumulative risk assessments. For 
most pesticides, although the Agency has some information in its files 
that may turn out to be helpful in eventually determining whether a 
pesticide shares a common mechanism of toxicity with any other 
substances, EPA does not at this time have the methodologies to resolve 
the complex scientific issues concerning common mechanism of toxicity 
in a meaningful way.
    There are no other pesticidal compounds that appear to be 
structurally, closely related to pyriproxyfen and may have similar 
effects on animals. In consideration of potential cumulative effects of 
pyriproxyfen and other substances that may have a common mechanism of 
toxicity, there are currently no available data or other reliable 
information indicating that any toxic effects produced by pyriproxyfen 
would be cumulative with those of other chemical compounds. Thus, only 
the potential risks of pyriproxyfen have been considered in this 
assessment of aggregate exposure and effects.
    Valent will submit information for EPA to consider concerning 
potential cumulative effects of pyriproxyfen consistent with the 
schedule established by EPA at 62 FR 42020 (Aug. 4, 1997) (FRL-5734-6) 
and other EPA publications pursuant to the Food Quality Protection Act.

E. Safety Determination

    1. U.S. population. Based on a complete and reliable toxicity 
database, EPA has established an RfD value of 0.35 mg/kg bw/day using 
the NOEL from the chronic rat feeding study and a 100-fold uncertainty 
factor.
    i. Chronic. The aggregate chronic exposure to pyriproxyfen will 
utilize much less than 0.1% of the RfD for the U.S. population. Because 
estimated exposures are far below 100% of the RfD, Valent concludes 
that there is a reasonable certainty that no harm will result from 
chronic aggregate exposure to pyriproxyfen residues.
    ii. Acute. Assessment of aggregate acute exposure to food and non-
food uses of pyriproxyfen to the U.S. population and numerous sub-
populations has demonstrated that exposures are small. MOE values using 
very conservative assumptions and a conservative toxicity endpoint are 
all greater than 100 and it can be concluded that there is reasonable 
certainty of no harm from acute exposures to pyriproxyfen.
    2. Infants and children-- i. Chronic. Using the same conservative 
exposure assumptions as for the general population, the percent of the 
RfD utilized by aggregate chronic exposure to residues of pyriproxyfen 
is 0.021% for Non-Nursing Infants, and 0.029% for Children (1 - 6 
Years), the most highly exposed child population subgroup. Because 
estimated exposures to infants and children are far below 100% of the 
RfD, Valent concludes that there is a reasonable certainty that no harm 
will result from chronic aggregate exposure to pyriproxyfen residues.
    ii. Acute. Assessment of aggregate acute exposure to food and non-
food uses of pyriproxyfen to infants and children has demonstrated that 
exposures allow calculation of acceptable MOE values. Using very 
conservative assumptions and a

[[Page 11252]]

conservative toxicity endpoint are all MOE values are greater than 100. 
Therefore, it can be concluded that there is reasonable certainty of no 
harm to infants and children from potential acute exposures to 
pyriproxyfen.
    3. Additional safety factor to provide additional protection to 
infants and children. Pyriproxyfen is supported by a complete, reviewed 
and reliable toxicology database. The toxicology of pyriproxyfen has 
been extensively evaluated in acute, sub-chronic, chronic, 
developmental, and reproductive toxicology studies including detailed 
histopathology of numerous tissues. The results of these studies show 
no evidence of any unique pathology or other effects to fetal or 
developing young experimentsl animals. In all these studies there is no 
indication that young or developing animals are any more sensitive to 
toxicity from pyriproxyfen or its metabolites than adult animals. The 
developmental toxicity studies and reproduction study all demonstrated 
that any toxicity attributable to pyriproxyfen was observed in adults 
at lower levels than in fetuses or in developing young animals. There 
is no indication that a higher safety factor, other than 100, is needed 
for additional protection for infants and children.

F. International Tolerances

    There are presently no Codex maximum residue levels established for 
residues of pyriproxyfen on any crop.

[FR Doc. 98-5985 Filed 3-5-98; 8:45 am]
BILLING CODE 6560-50-F