Fosetyl-Al - Pesticide Petition Filing 1/99
[Federal Register: January 29, 1999 (Volume 64, Number 19)]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
ENVIRONMENTAL PROTECTION AGENCY
Notice of Filing of Pesticide Petitions
AGENCY: Environmental Protection Agency (EPA).
SUMMARY: This notice announces the initial filing of pesticide
petitions proposing the establishment of regulations for residues of
certain pesticide chemicals in or on various food commodities.
DATES: Comments, identified by the docket control number PF-853, must
be received on or before March 1, 1999.
ADDRESSES: By mail submit written comments to: Information and Records
Integrity Branch, Public Information and Services Divison (7502C),
Office of Pesticides Programs, Environmental Protection Agency, 401 M
St., SW., Washington, DC 20460. In person bring comments to: Rm. 119,
CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
Comments and data may also be submitted electronically by following
the instructions under "SUPPLEMENTARY INFORMATION." No confidential
business information should be submitted through e-mail.
Information submitted as a comment concerning this document may be
claimed confidential by marking any part or all of that information as
"Confidential Business Information" (CBI). CBI should not be
submitted through e-mail. Information marked as CBI will not be
disclosed except in accordance with procedures set forth in 40 CFR part
2. A copy of the comment that does not contain CBI must be submitted
for inclusion in the public record. Information not marked confidential
may be disclosed publicly by EPA without prior notice. All written
comments will be available for public inspection in Rm. 119 at the
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays.
FOR FURTHER INFORMATION CONTACT: Hoyt Jamerson, Registration Support
Branch, Registration Division (7505), Office of Pesticide Programs,
Environmental Protection Agency, 401 M St., SW, Washington, DC 20460.
Office location, telephone number, and e-mail address: Rm. 268, Crystal
Mall #2, 1921 Jefferson Davis Highway, Arlington, VA 22202, (703) 308-
9368; e-mail: email@example.com.
SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions 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 these petitions
contain data or information regarding the elements set forth in section
408(d)(2); however, EPA has not fully evaluated the sufficiency of the
submitted data at this time or whether the data supports granting of
the petitions. Additional data may be needed before EPA rules on the
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-853] (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:
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-853) 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
Dated: January 21, 1999.
Director, Registration Division, Office of Pesticide Programs.
Summary of Petition
The petitioner summary of the pesticide petitions is printed below
as required by section 408(d)(3) of the FFDCA. The summary of the
petitions was prepared by the petitioner and represents the views of
the petitioner. EPA is publishing the petition summaries with minor
editing. 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.
Interregional Research Project Number 4 (IR-4)
PP 5E4434, 5E4559 and 7E4872,
EPA has received pesticide petitions (5E4434, 5E4559, and 7E4872)
from the Interregional Research Project Number 4 (IR-4), Center for
Minor Crop Pest Management, Technology Center of New Jersey, Rutgers,
the State University of New Jersey, 681 U.S. Highway # 1 South, North
Brunswick, NJ 08902-3390, proposing pursuant to section 408(d) of the
Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to
amend 40 CFR part 180 by establishing a tolerance for residues of the
fungicide aluminum tris (o-ethylphosphonate) (referred to in this
document as fosetyl-Al) in or on certain raw agricultural commodities
1. EPA has received an amendment to PP 5E4434 from IR-4 proposing
to amend the time-limited tolerance established for blueberries at 40
ppm. IR-4 requests that the tolerance for bluberries be amended by
extending the expiration date to December 31, 2000. The time extension
will allow IR-4 to develop additional magnitude of residue data in
support of a permanent tolerance for blueberries.
2. PP 5E4559 proposes the establishment of a tolerance for grapes
at 10 parts per million (ppm). Registration for use of fosetyl-Al on
grapes would be limited to areas east of the Rocky Mountains based on
the geographical representation of the residue data submitted.
3. PP 7E4872 proposes the establishment of a tolerance for
macadamia nuts at 0.3 ppm.
EPA has determined that the petitions 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
petitions. Additional data may be needed before EPA rules on the
A. Residue Chemistry
1. Plant metabolism. The metabolism of fosetyl-Al in plants is
adequately understood. Adequate data on the nature of the residues in
plants, including identification of major metabolites and degradates of
fosetyl-Al, are available. Radio labeled studies on the uptake,
translocation and metabolism in plants show that the chemical proceeds
through hydrolytic cleavage of the ethyl ester. The major residues are
fosetyl-Al, phosphorus acid and ethanol. The tolerances are established
for the parent only, that is fosetyl-Al. There is no reasonable
expectation of residues occurring in eggs, milk, and meat of livestock
and poultry since there are no livestock feed items associated with
commodities treated with fosetyl-Al.
2. Analytical method. Adequate methods are available for
enforcement purposes. There are two analytical methods acceptable for
determining residues of fosetyl-Al in plants: a gas chromatography
method is available for enforcement of tolerance in pineapple and is
listed as Method I in PAM, Vol. II; a gas chromatography/phosphorus
specific flame photometric detector (FPD-P) method (Rhone-Poulenc
Method No. 163) for citrus has undergone a successful method tryout on
oranges and has been sent to the FDA for inclusion in PAM as Method II.
B. Toxicological Profile
1. Acute toxicity. A complete battery of acute toxicity studies for
fosetyl-Al technical have been conducted. The acute oral rat and
primary dermal irritation studies indicate category IV toxicity. A
guinea pig dermal sensitization study shows fosetyl-Al is not a skin
sensitizer. The primary eye irritation study in rabbits shows fosetyl-
Al to be an eye irritant with Category I toxicity.
2. Genotoxicty. Fosetyl-Al is neither mutagenic nor genotoxic. The
genetic toxicity potential of fosetyl-Al was assessed in several
3. Reproductive and developmental toxicity. Rhone-Poulenc concludes
that fosetyl-Al is not a reproductive toxicant and shows no evidence of
estrogenic or androgenic related effects.
i. In a 3-generation reproduction study, fosetyl-Al was
administered to rats at dietary levels of 0, 6,000, 12,000 or 24,000
ppm. No adverse effects on reproductive performance or pup survival
were observed in any dose group. The lowest-observed adverse effect
level (LOAEL) was established at 12,000 ppm based on effects on animal
weights and urinary tract changes. The no-observed adverse effect level
(NOAEL) for all effects was 6,000 ppm.
ii. A teratology study in rats dosed via oral gavage at 500, 1,000
or 4,000 milligrams/kilogram/day (mg/kg/day) showed a developmental
NOAEL of 1,000 mg/kg. At 4,000 mg/kg, there was maternal toxicity, as
evidenced by effects on animal weights, maternal deaths, increased
resorptions and delayed fetal ossification.
iii. A rabbit teratology study showed no toxic effects at oral
doses up to 500 mg/kg.
Effects of fosetyl-Al on fetal development were observed only in
the rat at a dose producing severe maternal toxicity. In the absence of
maternal toxicity, NOAEL on fetal development were observed, i.e. at
1,000 mg/kg/day in rats or at 500 mg/kg/day in rabbits.
4. Subchronic toxicity. In subchronic studies, no significant
toxicity was observed even at doses exceeding the limit of 1,000 mg/kg/
5. Chronic toxicity. Chronic feeding studies have been conducted in
dogs and rats. The LOAEL for chronic effects of fosetyl-Al is 10,000
ppm (250 mg/kg/day) based on a 2 year feeding study with dogs fed diets
containing 0, 10,000, 20,000 and 40,000 ppm. This NOAEL is based on a
slight degenerative effect on the testes at the 20,000 ppm dose level.
In the rat, calculi in the urinary bladder and related
histopathological changes in the bladder and kidneys of males and
females were observed at 30,000/40,000 ppm (1,500/2,000 mg/kg/day).
6. Carcinogenicity. Long-term feeding studies were conducted with
technical grade fosetyl-Al in mice and rats and with monosodium
phosphite, the primary urinary metabolite of fosetyl-Al, in rats. In
addition, a mechanistic study in rats was conducted with feeding levels
up to 50,000 ppm. Fosetyl-Al was administered via admixture in the diet
to CD rats at target levels of 0, 2,000, 8,000, and 30,000/40,000 ppm
for approximately 2 years. After 2 weeks at 40,000 ppm, this dietary
level was reduced to 30,000 ppm. Calculi in the urinary bladder were
observed for several male and female rats at 30,000/40,000 ppm.
Microscopic examination revealed transitional cell carcinomas and
papillomas in the urinary bladders of high dose males. In addition, a
statistically significant increase in adrenal pheochromocytomas (benign
and malignant combined) was observed in males at 8,000 and 30,000/
40,000 ppm. The adrenal slides were independently reread by two
consulting pathologists who found no significant dose-related increases
in the incidence of pheochromocytomas or hyperplasia.
A subsequent mechanistic study in rats conducted with dietary
levels of 8,000, 30,000 and 50,000 ppm demonstrated that the massive
doses of 30,000 and 50,000 ppm fosetyl-Al alter calcium/phosphorous
homeostasis resulting in severe acute renal injury, similar to that
observed in the chronic rat study, and the formation of calculi in
kidneys, ureters, and bladder. Under conditions of chronic exposure,
these effects could lead to the formation of bladder tumors as seen in
the chronic rat study. At 8,000 ppm, no evidence of renal injury was
observed, a result consistent with the absence of bladder tumors.
A carcinogenicity study in rats was conducted with monosodium
phosphite administered via dietary mixture at levels of 2,000, 8,000,
and 32,000 ppm. No evidence of oncogenicity was observed in this study.
A 2 year feeding/carcinogenicity study was conducted in mice fed diets
containing fosetyl-Al at 0, 2,500, 10,000, or 20,000/30,000 ppm. The
20,000 ppm dose was increased to 30,000 ppm during week 19 of the
study. The NOAEL for all effects was 20,000/30,000 ppm (3,000/4,500 mg/
kg/day). There were no carcinogenic effects observed under the
conditions of this study.
The Office of Pesticide Programs', Health Effects Division,
Carcinogenicity Peer Review Committee (CPRC) concluded that the
pesticidal use of fosetyl-Al is unlikely to pose a carcinogenic hazard
for humans given that; (i) tumors develop in rats under extreme
conditions that are unlikely to be achieved other than under laboratory
conditions (at a dose in excess of the OPP dose limit for
carcinogenicity studies); (ii) tumors in rats are believed to develop
only at doses that produce stones; (iii) human dietary exposure to
fosetyl-Al is only about one-500,000th of the NOAEL for stone formation
in the rat (the most sensitive experimental model); and (iv) the dose
of fosetyl-Al which can be absorbed dermally by applicators is also
probably too low to result in stone formation. EPA has therefore chosen to use
the Reference Dose (RfD) to quantify dietary risk to humans.
7. Animal metabolism. Rat metabolism studies showed that most of
the radiolabel rapidly appeared in exhaled carbon dioxide. There was
also some radiolabel excreted in the urine as phosphite, along with a
smaller amount as the unchanged parent compound. It appears that
fosetyl-Al is essentially completely absorbed after ingestion and
extensively hydrolyzed to carbon dioxide which is exhaled. The
phosphite is excreted in the urine without further oxidation to
phosphate. Aluminum does not appear to be absorbed to a significant
extent from the gastrointestinal tract.
8. Metabolite toxicology. There are no metabolites of toxicological
concern. The tolerances are established for the parent only, that is
9. Endocrine disruption. No evidence of estrogenic or androgenic
effects were noted in any study with fosetyl-Al. NOAEL on mating or
fertility indices and gestation, live birth, or weaning indices were
noted in a 3-generation rat reproduction study at doses well above
EPA's limit of 1,000 mg/kg/day. Therefore, Rhone-Poulenc concludes that
fosetyl-Al does not have any effect on the endocrine system.
C. Aggregate Exposure
1. Dietary exposure--i. Food. The calculated potential dietary
exposure for the U.S. population is 0.065760 milligram/kilogram/
bodyweight/day (mg/kg/bwt/day). Potential exposure for nursing and non-
nursing infants less than 1-year old, children aged 1 to 6 years, and
children aged 7 to 12 years is calculated to be 0.134076, 0.116682, and
0.069637 mg/kg/bwt/day, respectively. Chronic dietary exposure was
estimated using established and proposed tolerance residue levels, 1987
food consumption data, and 100% crop treated.
ii. Drinking water. There is no established maximum contaminant
level (MCL) or health advisory level (HAL) for fosetyl-Al. Rhone-
Poulenc expects the potential for ground water and/or surface water
contamination by fosetyl-Al and its degradates to be very low, in most
cases, due to the rapid degradation of the compound in soil to non-
toxic degradates under both aerobic and anaerobic conditions. Under
aerobic laboratory conditions, the half-life of fosetyl-Al is between 1
and 1.5 hours in loamy sand, silt loam and clay loam and 20 minutes in
sandy loam soil. The degradation proceeds through the hydrolysis of the
ethyl ester bond, resulting in the formation of phosphorous acid and
ethanol. The ethanol is further degraded into carbon dioxide. An
anaerobic aquatic soil metabolism study was conducted. When anaerobic
conditions were established by flooding soil, the half-life was 40
hours with silty clay loam and 14 hours with sandy loam soil.
2. Non-dietary exposure. Considering that fosetyl-Al is applied by
commercial applicators on about 0.03% of available lawn acres (the
majority being commercial landscapes), the likelihood of post
application exposure occurring, particularly in a residential
situation, is extremely low. The use of fosetyl-Al by the homeowner
constitutes a minor use of the product since only small quantities are
expected to be sold in 1998. Other applications by professional
operators, e.g. golf courses, nurseries, sod farms, present only very
limited exposure to a limited population of adults but do not pose any
exposure to small children. Thus, Rhone-Poulenc concludes that the
ornamental and turf uses are not expected to add significantly to the
aggregate exposure for fosetyl-Al, and only dietary exposure has been
taken into consideration for risk assessment purposes.
D. Cumulative Effects
According to Rhone-Poulenc the effects associated with fosetyl-Al
are unlikely to be cumulative with any other compound. The formation of
calculi and bladder tumors in rats is the only significant
toxicological effect observed with fosetyl-Al. These effects were
observed in rat only at a dose which not only exceeds estimated human
exposure by several orders of magnitude but is in excess of the OPP
dose limit for carcinogenicity studies. Therefore, an aggregate
assessment based on common mechanisms of toxicity is not appropriate as
exposure to humans will be well below the levels producing calculi and
bladder tumors in rats. Further, considering the rapid elimination of
fosetyl-Al in the rat metabolism study, any effects associated with
fosetyl-Al are unlikely to be cumulative with any other compound. Based
on these reasons, only the potential risks of fosetyl-Al are considered
in the exposure assessment.
E. Safety Determination
1. U.S. population. EPA has established an RfD of 3.0 mg/kg/day
using a 100 fold safety factor and a NOAEL of 250 mg/kg/bodyweight/day
from the two year feeding study in dogs. A chronic dietary risk
assessment using established and proposed tolerance residue levels
results in utilization of 2.2, 4.5, 3.9, and 2.3% of the RfD for the
whole U.S. population, non-nursing infants less than 1 year old,
children aged 1 to 6 years, and children aged 7 to 12 years,
respectively. Thus, the dietary exposure for fosetyl-Al is well below
the RfD of 3.0 mg/kg/day and is negligible for all segments of the
population including infants and children. Based on a lack of acute
toxicity and the large margins of exposure (MOE) in the chronic dietary
assessment, Rhone-Poulenc concludes that fosetyl-Al does not pose any
acute dietary risks.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of fosetyl-Al, the
available developmental and reproductive toxicity studies and the
potential for endocrine modulation were considered.
Developmental toxicity studies in two species indicate that
fosetyl-Al has no teratogenic potential at any dose level. Further,
NOEAL on fetal development were observed in rabbits at doses up to 500
mg/kg/day or in rats at doses up to 1,000 mg/kg/day. In a 3-generation
rat reproduction study, NOAEL on reproductive performance or pup
survival were observed up to 24,000 ppm (equivalent to a dose well
above EPA's limit dose (LTD) of 1,000 mg/kg/day). Maternal and
developmental NOAELs and LELs were comparable in all studies indicating
no increase susceptibility of developing organisms. Further, fosetyl-Al
has no endocrine-modulation characteristics as demonstrated by the lack
of endocrine effects in developmental, reproductive, subchronic, and
chronic studies. The probability of non-occupational sources of
exposure to fosetyl-Al is negligible. Therefore, based upon the
completeness and reliability of the toxicity data and the conservative
exposure assessment, Rhone-Poulenc concludes that there is a reasonable
certainty that no harm will result to infants and children from
exposure to the residues of fosetyl-Al and no additional uncertainty
factor is warranted.
F. International Tolerances
There are presently no Codex maximum residue levels established for
residues of fosetyl-Al on any crop.
[FR Doc. 99-2202 Filed 1-28-99; 8:45 am]
BILLING CODE 6560-50-F