[Federal Register Volume 66, Number 239 (Wednesday, December 12, 2001)]
[Notices]
[Pages 64251-64257]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-30371]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-1053; FRL-6809-8]
Notice of Filing of a Pesticide Petition to Establish a Tolerance
for a Certain Pesticide Chemical in or on Food
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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SUMMARY: This notice announces the initial filing of a pesticide
petition proposing the establishment of regulations for residues of a
certain pesticide chemical in or on various food commodities.
DATES: Comments, identified by docket control number PF-1053, must be
received on or before January 11, 2002.
ADDRESSES: Comments may be submitted by mail, electronically, or in
person. Please follow the detailed instructions for each method as
provided in Unit I.C. of the SUPPLEMENTARY INFORMATION. To ensure
proper receipt by EPA, it is imperative that you identify docket
control number PF-1053 in the subject line on the first page of your
response.
FOR FURTHER INFORMATION CONTACT: By mail: Carol E. Frazer PhD.,
Biopesticides and Pollution Prevention Division, (7511), Office of
Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania
Ave., NW., Washington, DC 20460; telephone number: (703) 308-8810; e-
mail address: [email protected].
SUPPLEMENTARY INFORMATION:
I. General Information
A. Does this Action Apply to Me?
You may be affected by this action if you are an agricultural
producer, food manufacturer or pesticide manufacturer. Potentially
affected categories and entities may include, but are not limited to:
------------------------------------------------------------------------
Examples of
Categories NAICS Codes potentially
affected entities
------------------------------------------------------------------------
Industry 111 Crop production
112 Animal production
311 Food manufacturing
32532 Pesticide
manufacturing
------------------------------------------------------------------------
This listing is not intended to be exhaustive, but rather provides
a guide for readers regarding entities likely to be affected by this
action. Other types of entities not listed in the table could also be
affected. The North American Industrial Classification System (NAICS)
codes have been provided to assist you and others in determining
whether or not this action might apply to certain entities. If you have
questions regarding the applicability of this action to a particular
entity, consult the person listed under FOR FURTHER INFORMATION
CONTACT.
B. How Can I Get Additional Information, Including Copies of this
Document and Other Related Documents?
1. Electronically. You may obtain electronic copies of this
document, and certain other related documents that might be available
electronically, from the EPA Internet Home Page at http://www.epa.gov/.
To access this document, on the Home Page select ``Laws and
Regulations,'' ``Regulations and Proposed Rules,'' and then look up the
entry for this document under the ``Federal Register--Environmental
Documents.'' You can also go directly to the Federal Register listings
at http://www.epa.gov/fedrgstr/.
2. In person. The Agency has established an official record for
this action under docket control number PF-1053. The official record
consists of the documents specifically referenced in this action, any
public comments received during an applicable comment period, and other
information related to this action, including any information claimed
as confidential business information (CBI). This official record
includes the documents that are physically located in the docket, as
well as the documents that are referenced in those documents. The
public version of the official record does not include any information
claimed as CBI. The public version of the official record, which
includes printed, paper versions of any electronic comments submitted
during an applicable comment period, is available for inspection in the
Public Information and Records Integrity Branch (PIRIB), Rm. 119,
Crystal Mall #2, 1921 Jefferson Davis Highway, Arlington, VA, from 8:30
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The
PIRIB telephone number is (703) 305-5805.
C. How and to Whom Do I Submit Comments?
You may submit comments through the mail, in person, or
electronically. To ensure proper receipt by EPA, it is imperative that
you identify docket control number PF-1053 in the subject line on the
first page of your response.
1. By mail. Submit your comments to: Public Information and Records
Integrity Branch (PIRIB), Information Resources and Services Division
(7502C), Office of Pesticide Programs (OPP), Environmental Protection
Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460.
2. In person or by courier. Deliver your comments to: Public
Information and Records Integrity Branch (PIRIB), Information Resources
and Services Division (7502C), Office of Pesticide Programs (OPP),
Environmental Protection Agency, Rm. 119, Crystal Mall #2, 1921
Jefferson Davis Highway, Arlington, VA. The PIRIB is open from 8:30
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The
PIRIB telephone number is (703) 305-5805.
3. Electronically. You may submit your comments electronically by
e-mail to: [email protected], or you can submit a computer disk as
described above. Do not submit any information electronically that you
consider to be CBI. Avoid the use of special characters and any form of
encryption. Electronic submissions will be accepted in Wordperfect 6.1/
8.0 or ASCII file format. All comments in electronic form must be
identified by docket control number PF-1053. Electronic comments may
also be filed online at many Federal Depository Libraries.
D. How Should I Handle CBI That I Want to Submit to the Agency?
Do not submit any information electronically that you consider to
be CBI. You may claim information that you submit to EPA in response to
this document as CBI by marking any part or all of that information as
CBI. Information so marked will not be disclosed except in accordance
with procedures set forth in 40 CFR part 2. In addition to one complete
version of the comment that includes any information claimed as CBI, a
copy of the comment that does not contain the information claimed as
CBI must be submitted for inclusion in the public version of the
official record. Information not marked confidential
[[Page 64252]]
will be included in the public version of the official record without
prior notice. If you have any questions about CBI or the procedures for
claiming CBI, please consult the person identified under FOR FURTHER
INFORMATION CONTACT.
E. What Should I Consider as I Prepare My Comments for EPA?
You may find the following suggestions helpful for preparing your
comments:
1. Explain your views as clearly as possible.
2. Describe any assumptions that you used.
3. Provide copies of any technical information and/or data you used
that support your views.
4. If you estimate potential burden or costs, explain how you
arrived at the estimate that you provide.
5. Provide specific examples to illustrate your concerns.
6. Make sure to submit your comments by the deadline in this
notice.
7. To ensure proper receipt by EPA, be sure to identify the docket
control number assigned to this action in the subject line on the first
page of your response. You may also provide the name, date, and Federal
Register citation.
II. What Action is the Agency Taking?
EPA has received a pesticide petition as follows proposing the
establishment and/or amendment of regulations for residues of a certain
pesticide chemical in or on various food commodities under section 408
of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a.
EPA has determined that this petition contains data or information
regarding the elements set forth in section 408(d)(2); however, EPA has
not fully evaluated the sufficiency of the submitted data at this time
or whether the data support granting of the petition. Additional data
may be needed before EPA rules on the petition.
List of Subjects
Environmental protection, Agricultural commodities, Feed additives,
Food additives, Pesticides and pests, Reporting and recordkeeping
requirements.
Dated: November 27, 2001.
Janet L. Andersen,
Director, Biopesticides and Pollution Prevention Division, Office of
Pesticide Programs.
Summary of Petition
The petitioner summary of the pesticide petition is printed below
as required by section 408(d)(3) of the FFDCA. The summary of the
petition was prepared by the petitioner and represents the view of the
petitioners. EPA is publishing the petition summary verbatim without
editing it in any way. The petition summary announces the availability
of a description of the analytical methods available to EPA for the
detection and measurement of the pesticide chemical residues or an
explanation of why no such method is needed.
EPA has received a pesticide petition (PP) 1F6314 from 3M, St.
Paul, Minnesota 55144-1000, 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 to establish an exemption from the requirement of
a tolerance for the biochemical pesticides the C8,
C10 and C12 saturated fatty acid monoesters of
glycerol and propylene glycol in or on all raw agricultural commodities
and food.
Pursuant to section 408(d)(2)(A)(i) of the FFDCA, as amended, 3M
has submitted the following summary of information, data, and arguments
in support of their pesticide petition. This summary was prepared by 3M
and EPA has not fully evaluated the merits of the pesticide petition.
The summary may have been edited by EPA if the terminology used was
unclear, the summary contained extraneous material, or the summary
unintentionally made the reader conclude that the findings reflected
EPA's position and not the position of the petitioner.
3M
PP 1F6314
A. Product Name and Proposed Use Practices
3M's VWX-42 Technology System is comprised of six very closely
related active ingredients that are used singly or in combination
against Gram positive and Gram negative bacteria, fungi, yeasts and
lipid coated viruses to control spoilage of food and feed crops after
harvest. The choice of which active ingredient or mix of ingredients to
use is determined by the identity of the pest organisms to be
controlled and the characteristics desired for the end-use formulation.
The active ingredients are generally applied at levels between 0.1% and
1% in the diluted formulation at a rate sufficient to wet thoroughly
the commodity being treated.
B. Product Identity/Chemistry
1. Identity of the pesticide and corresponding residues. The
Chemical Abstract Services (CAS) index names for the six active
ingredients are as follows:
Octanoic acid, monoester with 1,2,3-propanetriol, CAS
Registry No. 26402-26-6;
Decanoic acid, monoester with 1,2,3-propanetriol, CAS
Registry No. 26402-22-2;
Dodecanoic acid, monoester with 1,2,3-propanetriol, CAS
Registry No. 27215-38-9;
Octanoic acid, monoester with 1,2-propanediol, CAS
Registry No. 68332-79-6;
Decanoic acid, monoester with 1,2-propanediol, CAS
Registry No. 68795-69-7; and
Dodecanoic acid, monoester with 1,2-propanediol, CAS
Registry No. 27194-74-7.
The residues expected in treated raw agricultural commodities and
food are the parent compounds and/or their hydrolysis products
(metabolites). The hydrolysis products are a mixture of the free fatty
acid and glycerol or propylene glycol. The glycerol fatty acid
monoesters are natural components in dietary fats and natural breakdown
products from the metabolism of fat (triacylglycerol) in all living
systems. The propylene glycol monoesters are metabolized by the same
pathways and with the same ease as glycerol. Both types of active
ingredient are metabolized by living matter as food. The first step in
their metabolism is hydrolysis to free fatty acid and glycerol or
propylene glycol.
2. Magnitude of residue at the time of harvest and method used to
determine the residue. An unreasonable worst cast physical model was
constructed to generate the residue data. A typical end-use formulation
was prepared containing one of the active ingredients. A typical
diluted treatment solution (0.86% active ingredient by weight) was
prepared by diluting the formulation with water. Eighteen different raw
agricultural commodities were obtained from local supermarkets in St.
Paul, Minnesota and treated with the diluted formulation by soaking at
room temperature for 15 minutes. Ten samples of each commodity were
weighed to the nearest milligram before treatment and allowed to drain
on a wire grate for 1 minute before reweighing. The difference between
pre- and post-soak weights was used as the measure of residue for each
commodity sample.
The commodities obtained from supermarket shelves, particularly
beans, had inevitably lost moisture between the time of harvest and the
time when they were treated to generate residue data. The treatment
solution, being
[[Page 64253]]
aqueous, under the test conditions replaced moisture lost since
harvest. In some cases, the absorption of the diluted aqueous pesticide
formulation by the commodity was substantially greater than what would
be expected if it had been treated immediately after harvest and
treated by wetting its surface rather than soaking. Although certain
residue levels determined by our worst-case physical model were clearly
excessive, all of the experimentally determined values were included in
the dietary analysis in keeping with the intended worst-case nature of
the assessment. The experimentally determined residue levels used in
the aggregate dietary risk assessment ranged from 10 to 400 parts per
million (ppm) (milligrams/kilograms (mg/kg) commodity) active
ingredient residue.
3. A statement of why an analytical method for detecting and
measuring the levels of the pesticide residue are not needed. An
exemption from tolerance is sought because use of the VWX-42 Technology
System active ingredients will create only minuscule exposures (< 1 mg/
kg-bodyweight (bwt)/day) when compared to the natural levels of such
compounds in living tissue and in foods (~50-100 grams per/day (g/
day)), and compared to the levels permitted in food as direct additives
(g/day). Hence, there will be no need to monitor for pesticide residues
and there is no need for an analytical method for detecting and
measuring such residues in the commodities treated.
C. Mammalian Toxicological Profile
A substantial body of primary toxicology data were generated to
support EPA registration as biochemical pesticides. In all studies,
EPA's limit doses were used and the test compounds were found to be
safe, but all tests were not conducted on all 6 active ingredients.
Propylene glycol monocaprylate (the C8 ester) was selected
as the test material to represent all 6 active ingredients in
subchronic testing (90-day rat oral toxicity study). Because the
metabolism and toxicity of the VWX-42 Technology System active
ingredients have been well documented in the scientific literature and
all six active ingredients are known to be identical with respect to
toxicity and metabolism, a new 90-day study was conducted on only 1 of
the 6 active ingredients. A full acute toxicity test battery (6
studies) was generated on the C8 propylene glycol monoester
and on the C12 glycerol ester, thereby bounding the chemical
structures of all 6 ingredients.
The results of the individual studies are summarized below.
1. Acute oral toxicity (rat) for glycerol monolaurate: Non-toxic. A
group of 6 fasted rats (3 male and 3 female) received a single oral
gavage dose of glycerol monolaurate, formulated in corn oil and
administered at a dose level of 5,000 mg/kg bwt, in a limit test. No
abnormalities were revealed in any of the animals at the macroscopic
examination at study termination on Day 15.
The acute lethal oral dose to rats was demonstrated to be greater
than 5,000 mg/kg.
2. Acute oral toxicity (rat) for propylene glycol monocaprylate:
Non-toxic. A group of 6 fasted rats (3 males and 3 females) received a
single oral gavage dose of the test substance administered at a dosage
of 5,000 mg/kg bwt. Clinical signs of reaction to treatment were
confined to piloerection (all rats) and increased salivation (one
female only), both evident within a few minutes of dosing with only
piloerection persistent during the remainder of Day 1. There were no
signs of reaction to treatment and piloerection had resolved by Day 2
in female rats and by Day 4 in male rats. No abnormalities were
revealed in any of the animals at the macroscopic examination at study
termination on Day 15.
The acute lethal oral dose to rats of propylene glycol
monocaprylate was demonstrated in this study to be greater than 5,000
mg/kg bwt.
3. Acute dermal toxicity (rat) for glycerol monolaurate: Non-toxic.
A group of 10 rats (5 males and 5 females) received a single topical
application of glycerol monolaurate formulated in corn oil and
administered at a dosage of 5,000 mg/kg bwt. There were no clinical
signs of reaction to treatment observed in any animal throughout the
study. All animals were killed as scheduled at study termination (Day
15) and subjected to a macroscopic examination. No macroscopic
abnormalities were observed for animals killed at study termination on
Day 15.
The acute lethal dermal dose to rats of glycerol monolaurate was
demonstrated to be greater than 5,000 mg/kg bwt.
4. Acute dermal toxicity (rat) for propylene glycol monocaprylate:
Non-toxic. A study was performed to assess the acute dermal toxicity of
propylene glycol monocaprylate to the rat. A group of 10 rats (5 males
and 5 females) received a single topical application of the test
substance at a dosage of 5,000 mg/kg bwt. All animals were killed as
scheduled at study termination (Day 15) and subjected to a macroscopic
examination. No macroscopic abnormalities were observed for animals
killed at study termination on Day 15.
The acute lethal dermal dose to rats of propylene glycol
monocaprylate was demonstrated to be greater than 5,000 mg/kg bwt.
5. Acute inhalation (rat) for glycerol monolaurate: Harmless by
inhalation. In all instances, the aerosol generator was blocked
following the start of generation. The waxiness of glycerol monolaurate
made it impossible to generate aerosols. Because respirable particles
cannot be produced from such low melting waxy materials, the test
substance is considered harmless by the inhalation route of exposure
under normal handling conditions.
6. Acute inhalation (rat) for propylene glycol monocaprylate: Non-
toxic. The acute toxicity of propylene monocaprylate was assessed by
exposing a group of rats (5 males and 5 female), for a period of 4
hours, to a droplet aerosol generated from the test substance at a
target concentration of 5 mg/L. Another group (5 male and 5 female),
acting as a control was exposed to clean dry air only. The nominal
concentration of propylene monocaprylate was 5.6 mg/L. The mass median
aerodynamic (MMAD) was 2.0 m and was within the ideal range (1
m to 4 m) for an acute inhalation study.
Approximately 88% of the particles were considered of a respirable size
(< 7 m in aerodynamic diameter). The LC5O (4-hour
inhalation) for propylene glycol monocaprylate, is in excess of 4.92
mg/L (4920 ppm) in air. EPA's limit dose for this test is 2 mg/L.
7. Eye irritation (rabbit) for glycerol monolaurate: Slight
irritant. Three rabbits were each administered a single ocular dose of
0.1 mL of the test substance (mean weight 60 mg) and observed for up to
7 days after instillation. The instillation in one animal elicited a
corneal lesion and iritis (both Graded 1) 48 hours post dose. All 3
rabbits exhibited transient conjunctival inflammation (up to Grade 3).
Resolution was complete in two instances within approximately 72 hours
of dosing and in one animal 7 days after dosing. The test material is
considered a slight eye irritant.
8. Eye irritation (rabbit) for propylene glycol monocaprylate: Non-
irritant. Three rabbits were each administered a single ocular dose of
0.1 mL of propylene glycol monocaprylate test substance and observed
for three days after instillation. The single instillation of propylene
glycol monocaprylate elicited in two of the three rabbits a transient,
slight to well-defined conjunctival irritation only. The test
[[Page 64254]]
substance is not considered an ocular irritant.
9. Skin irritation (rabbit) for glycerol monolaurate: Non-Irritant.
Three rabbits were each administered a single dermal dose of 0.5 gm of
the test substance glycerol monolaurate, under semi-occlusive
conditions for 4 hours and observed for up to 11 days. The test
material produced transient slight erythema only in one animal. The
test substance is not considered a dermal irritant.
10. Skin irritation (rabbit) for propylene glycol monocaprylate:
Non-irritant. Three rabbits were each administered a single dermal dose
of 0.5 mL of the test substance propylene glycol monocaprylate under
semi-occlusive conditions for 4 hours and observed for up to 11 days.
Propylene glycol monocaprylate produced only slight erythema in all
animals. The test substance is not considered a dermal irritant.
11. Skin sensitization (guinea-pig) for glycerol monolaurate: Non-
sensitizer. Guinea pigs were dosed by intradermal injection and topical
application. Based on the results of a preliminary study and in
compliance with regulatory guidelines, the following dose levels were
selected:
Intradermal injection: 2.5% w/v in sterile water
Topical application: 10% w/v in sterile water
Challenge applications: 0.5 and 1% w/v in sterile water
Ten test and five control guinea pigs were used in this study.
Following the first challenge application, negative responses were
observed in six test animals, inconclusive responses were seen in three
animals and a positive response was observed in the remaining test
animal. A second challenge was conducted to clarify these reactions.
Following the second challenge application glycerol monolaurate did not
produce dermal reactions in any of the test or control animals.
Glycerol monolaurate is not considered to have the potential to cause
skin sensitization.
The sensitivity of the guinea-pig strain used by the laboratory is
checked periodically with a weak/moderate sensitizer - hexyl cinnamic
aldehyde (HCA). In this study HCA produced evidence of skin
sensitization (delayed contact hypersensitivity) in nine of the ten
animals, thus confirming the sensitivity and reliability of the
experimental technique.
12. Skin sensitization (guinea-pig) for propylene glycol
monocaprylate: Potential sensitizer. The guinea pigs were dosed by
intradermal injection and topical application. Based on the results of
a preliminary study and in compliance with the regulatory guidelines,
the following dose levels were selected:
Intradermal injection: 0.5% v/v in sterile water
Topical application: as supplied
Challenge application: 25 and 50% v/v in sterile water
Ten test and five control guinea pigs were used in this study. In
this study propylene glycol monocaprylate produced evidence of skin
sensitization (delayed contact hypersensitivity) in all of the test
animals. Propylene glycol monocaprylate is considered to have the
potential to cause skin sensitization. Propylene glycol itself is known
to cause allergic reactions in patients receiving medical treatments
containing this substance.
The sensitivity of the guinea-pig strain used was checked
periodically by the laboratory with a weak to moderate sensitizer -
hexyl cinnamic aldehyde (HCA). In this study HCA produced evidence of
skin sensitization (delayed contact hypersensitivity) in nine of the
ten animals, thus confirming the sensitivity and reliability of the
experimental technique.
13. 28-Day oral (rat): for propylene glycol monocaprylate: Non-
toxic. The effects of propylene glycol monocaprylate (T-7475.8) were
assessed in rats (groups of 5 males and 5 females) by oral gavage
administration once a day for 4 weeks, employing dose levels of 0, 500,
750 or 1,000 mg/kg/day. Doses up to 1,000 mg/kg/day were well tolerated
with the only effects noted being higher protein and albumin values and
a higher lung and liver weight, all in females. In the absence of
histopathological examination, the toxicological importance of these
findings is unclear. However, it was considered that 1,000 mg/kg/day
was well tolerated and that it would be suitable for use as a high dose
level in the subsequent 13 week toxicity study.
14. 13-Week oral (rat) for propylene glycol monocaprylate: Non-
toxic. The systemic toxicity of propylene glycol monocaprylate (T-
7475.8) was assessed in groups of rats (20 males and 20 females per
group) by oral (gavage) administration at 0, 100, 500, and 1,000 mg/kg/
day dose levels for 13 weeks. There were no unscheduled deaths in any
of the groups and clinical observation, neurotoxicity, metabolic
parameters and organ histopathology indicated no changes of
toxicological significance. It was concluded that a dosage of 1,000 mg/
kg/day was considered to be a no observable adverse effect level
(NOAEL) for both sexes.
Waivers of genotoxicity, reproductive and developmental toxicity
studies were also requested on the bases described below.
15. Genotoxicity. Because the VWX-42 active ingredients themselves
in vertebrate systems are immediately metabolized like any fats to
polyols and free fatty acids, upon ingestion they become
indistinguishable from the natural background of such compounds in
living systems. Polyols and free fatty acids in living systems are not
genotoxic. Hence, waivers were requested for all genotoxicity testing
requirements on the basis that conducting such tests would not be of
value to EPA in its evaluation of risks. The VWX-42 active ingredients
are already known, from a metabolic standpoint, not to be genotoxic.
16. Reproductive and developmental toxicity. Also on the basis of
their metabolism, the VWX-42 active ingredients, and their natural
breakdown products, are known not to be reproductive or developmental
toxicants. Waivers were requested for all such testing requirements on
the basis that conducting such tests would not be of value to EPA in
its evaluation of risks.
17. Scientific literature on toxicity and metabolism. Basic
toxicity testing on mono and diacylglycerols and saturated fatty acids
was done in the 1930-1960 period. The available data include extensive
testing in intermediate and long-term studies. Less work has been
published on propylene glycol saturated fatty acid esters, but the
available data are adequate to demonstrate an equivalence between
propylene glycol esters and acylglycerols. Comprehensive reviews are
available prepared by a number of sources including the Food and Drug
Administration (FDA) and the Food and Agricultural Organization of the
United Nations (FAO) and the World Health Organization (WHO) through
the Joint FAO/WHO Expert Committee on Food Additives (JECFA).
The NOAELs for mono acylglycerols, regardless of the saturated
fatty acid, are similar. Rats can be fed from 10-15% in the diet for a
lifetime without ill effects, dose levels corresponding to 5 g/kg-bwt/
day. Rats fed propylene glycol monosuccinate and monostearate at levels
up to 10% of the diet for six months showed no evidence of gross or
histological pathology attributable to treatment. Dogs fed at the same
levels for six months showed no signs of toxicity.
The particular fatty acid moiety in mono acylglycerols does not
matter because vertebrate systems are capable
[[Page 64255]]
of metabolizing each of the acids in the range of C8 to
C18 with equal facility. Oxidation of fatty acids is a
primary source of energy in vertebrate systems. Fatty acids are
supplied in the diet in the form of triacylglycerols (fats) which are
hydrolyzed by pancreatic lipase enzymes to form free fatty acids,
glycerol and mono acylglycerols. The VWX-42 gylcerol active ingredients
are indistinguishable from the natural acylglycerols and fatty acids
found in the intestine following ingestion of fats.
Specificity of the pancreatic lipase enzyme is independent of the
nature of the fatty acid. It is also not stereospecific in its action
and glycerol esters and propylene glycol esters are hydrolyzed by it
with equal facility.
Studies with 14C-labeled propylene glycol show that it
is readily absorbed from the gastrointestinal tract and rapidly
converted in the liver to 14C-glycogen or
14CO2. In a like manner, when 14C-
glycerol is administered to the rat, radiolabel appears in expired
CO2, blood glucose, liver glycogen, liver fat and liver
phosphatides within 15 minutes. Within 6 hours, 40% of the label is
contained in expired CO2 and the remainder is distributed
through the test animal. Very small amounts are excreted.
FDA has looked at metabolism of propylene glycol mono and
distearate as a model compounds to represent propylene glycol fatty
acids. In studies on radiolabeled propylene glycol distearate the rate
limiting factor in the metabolism was found to be hydrolysis of the
ester, which is complete in about 3 hours. In 5 hours, 94% of the
propylene glycol is absorbed and 94% of the absorbed material is found
in expired CO2 in 72 hours. The fatty acid portion of the
ester is absorbed and metabolized more slowly than the propylene
glycol. Only 51% of the stearic acid label was expired as
CO2 in the same period.
D. Aggregate Exposure
1. Dietary exposure. Aggregate dietary exposure estimates were
generated using EPA's Dietary Exposure Potential Model (DEPM)
customarily used by the agency in making such estimates. The model is
designed to generate dietary exposure estimates by combining data from
established food consumption data bases with residue data. In this
case, food consumption data came from the 10th National Food
Consumption Survey conducted during the three year period of 1994-1996
by the Agricultural Research Service of the U.S. Department of
Agriculture. These data are also known as the Continuing Survey of Food
Intake by Individuals, 1994-1996 (CSFII 1994-1996).
i. Food. Food residue estimates were generated for use in the DEPM
analysis to simulate very broad use of the VWX-42 active ingredients.
Specifically, residues estimates were constructed for all food
commodities corresponding to the 18 raw agricultural commodities (RACs)
for which residue data were generated for the following major food
groups:
Fruits;
Vegetables;
Beverages; and
Infant food.
In keeping with the worst case nature of the analysis, residue data
for a tested commodity was used also for similar commodities not tested
(e.g., spinach values were used for other delicate greens; kale values
were used for other heavy greens such as collard; peach values were
used for apricots). The assumption was also made that residue levels
are not changed by cooking and that fruit and vegetable mixtures
contain 50% of one or more RAC, unless the composition of the mixture
is specified.
Total dietary exposure estimates were generated using the model for
the U.S. population and 20 subpopulations, including non-nursing
infants and children. The subpopulation groups were defined by age,
gender, geographic location, ethnicity and income level. All
calculations represented residue levels assuming treatment of 100% of
every commodity consumed in the U.S. for which residue estimates could
be generated, another severe worst-case assumption. The model produced
data tables containing the consumption of each food, its assumed
residue level and the calculated exposure from that consumption in
g/kg-bwt/day for each of the subpopulations.
For all subpopulation groups, the commodity that contributed in the
analysis the most to exposure was cooked green beans. This result
reflects the fact that green beans absorbed an unexpectedly large
amount of treatment solution in the experimental procedure used to
generate RAC residue estimates. Based upon the worst-case data and
assumptions described above, the model calculated the highest exposure
of 0.5 mg/kg-bwt/day for non-nursing infants. Dietary exposure for the
total U.S. population was less than 0.2 mg/kg-bwt/day.
ii. Drinking water. All anticipated or proposed use for the VWX-42
active ingredients will be indoors and the active ingredients are not
soluble in water. Hence, drinking water is not a feasible route of
exposure.
2. Non-dietary exposure. The only non-dietary exposures from
pesticidal uses of the VWX-42 active ingredients will be occupational,
i.e., commercial applicator/mixer loader exposures. Occupational
exposures are not included under the FFDCA in the assessment of
aggregate exposures for the purpose of establishing tolerances and
exemptions from tolerance.
E. Cumulative Exposure
In assessing their cumulative effects, the VWX-42 active
ingredients are members of a much larger class of compounds that are
toxicologically and metabolically equivalent. This class of compounds
are dealt with by all vertebrate systems as food rather than toxicants.
Glycerol fatty acid monoesters are natural components in dietary fats
and natural breakdown products from metabolism of fat (triacylglycerol)
in all living systems. Fatty acid esters of propylene glycol also occur
as direct food additives in the human diet in substantial quantities.
Toxicologically and metabolically the glycerol and propylene glycol
esters are equivalent.
The proposed use of VWX-42 active ingredients as pesticides will
contribute a negligible amount (total U.S. population worst case
estimate <0.2 mg/kg/day) to the existing cumulative exposure to the
class of compounds when compared to natural levels of such compounds
and their metabolites in tissue and foods (50-100 g/day in humans for
glycerol esters), and to the levels permitted in food as direct
additives (grams per day).
F. Safety Determination
1. U.S. population. Generating a quantitative measure of safety,
such as a margin of exposure value (MOE), is difficult for the VWX-42
active ingredients because they function as foods rather than toxicants
in all test animal systems, giving no clear toxicity endpoints even
when tested at levels representing a substantial portion of the diet.
Both acute and subchronic primary data generated to support this
petition show no observed adverse effects at the limit doses
established for such tests by EPA. Subchronic and chronic exposure
studies reported in the literature run at much higher levels (e.g., 10%
or more of the total diet) also produced no adverse effects. In its
review of such compounds, the JECFA observed that ``dietary loads of a
food additive in excess of 10 percent are of little value in assessment
of safety-in-use...'', and the committee based its conclusion of safety
upon the biochemical and metabolic evidence that the breakdown
[[Page 64256]]
product of such additives are ``normal dietary constituents.''
MOE levels can be calculated for the U.S. population as shown below
in Table 1, using various NOAELs, including the NOAEL for the 90-day
gavage study submitted in support of this petition. These values
represent the highest levels tested, not the highest level tolerated
without adverse effects. JECFA has also established an allowable daily
intake value (ADI) for propylene glycol monostearate of 25 mg/kg-bwt/
day that may be used to derive an MOE estimate. The several MOE
calculations presented in Table 1 demonstrate that exposures, even when
estimated using severe worst-case assumptions, are well below any level
of concern.
Table 1. Calculated Margins of Exposure for VWX-42 Active Ingredients
----------------------------------------------------------------------------------------------------------------
Basis for calculation Acceptable level Estimated exposure Margin of exposure
----------------------------------------------------------------------------------------------------------------
NOAEL, 90-day gavage study using NOAEL = 1,000 mg/kg-bwt/ U.S. Population = 0.13 U.S. population = 7,690
propylene glycol monocaprylate day mg/kg-bwt/day
Non-nursing infants =
0.44 mg/kg-bwt/day.
----------------------------------------------------------------------------------------------------------------
FDA NOAEL, 90-day dietary study with NOAEL = 7.52% of diet Same as above U.S. population =
propylene glycol monostearate* (= highest dose tested 24,770
= 3.22 g/kg-bwt/day)
----------------------------------------------------------------------------------------------------------------
JECFA ADI for propylene glycol ADI = 25 mg/kg-bwt/day Same as above U.S. population =
monostearate* including safety 19,230
factor of 100
----------------------------------------------------------------------------------------------------------------
*Propylene glycol monostearate is widely accepted as a surrogate for all glycerol and propylene glycol
monoesters.
2. Infants and children. MOE levels for infants and children can be
calculated as shown in Table 2 using the same toxicity endpoints as for
the U.S. population.
Table 2. Calculated Margins of Exposure for VWX-42 Active Ingredients
----------------------------------------------------------------------------------------------------------------
Basis for calculation Acceptable level Estimated exposure Margin of exposure
----------------------------------------------------------------------------------------------------------------
NOAEL, 90-day garage study using NOAEL = 1,000 mg/kg-bwt/ Non-nursing infants = Non-nursing infants =
propylene glycol monocaprylate day 0.44 mg/kg-bwt/day 2,270
Children 1-6 = 0.28 mg/ Children 1-6 = 3,570
kg-bwt/day. Children 7-12 = 6,670
Children 7-12 = 0.15 mg/
kg-bwt/day.
----------------------------------------------------------------------------------------------------------------
FDA NOAEL, 90-day dietary study with NOAEL = 7.52% of diet Same as above Non-nursing infants =
propylene glycol monostearate* (= highest dose tested 7,320
= 3.22 g/kg-bwt/day) Children 1-6 = 11,500
Children 7-12 = 21,470
----------------------------------------------------------------------------------------------------------------
JECFA ADI for propylene glycol ADI = 25 mg/kg-bwt/day, Same as above Non-nursing infants =
monostearate* including safety 5,680
factor of 100 Children 1-6 = 8,930
Children 7-12 = 16,670
----------------------------------------------------------------------------------------------------------------
*Propylene glycol monostearate is widely accepted as a surrogate for all glycerol and propylene glycol
monoesters.
G. Effects on the Immune and Endocrine Systems
Because VWX-42 active ingredients in vertebrate systems are
immediately metabolized, like any fat, to polyols and free fatty acids,
upon ingestion they become indistinguishable from the natural
background of such compounds in living systems. On the basis that they
are natural components of vertebrate systems, the VWX-42 active
ingredients, and their breakdown products, are not expected to have any
effect on immune and endocrine systems.
H. Existing Tolerances
No tolerances exist for any of the VWX-42 Technology System
compounds as pesticide active ingredients. They may be used as inert
ingredients in pesticide formulations and many clearances exist under
the FFDCA for their use as direct and indirect food additives.
Mono and diglycerides from fats or oils or fat-forming acids are
affirmed as GRAS as direct food additives under 21 CFR 184.1505. Mono
and diglycerides of C8-C14 fatty acids are exempt
from the requirement for tolerance under 40 CFR 180.1001(c) for use as
surfactants and adjuvants in pesticide formulations. Numerous fatty
acids, the hydrolysis products of both the glycerol and propylene
glycol esters, are themselves also affirmed as GRAS (21 CFR 184.1025).
Propylene glycol mono and diesters of fatty acids are permitted
under 21 CFR 172.856 for general use in food; 21 CFR 172.860 permits
the corresponding fatty acid metabolites in foods; and 21 CFR 172.863
permits salts of fatty acids in food. The monoesters are also permitted
under 21 CFR 175.105 as ingredients in adhesives used in food contact
applications. Propylene glycol esters of fatty acids are also cleared
by USDA as emulsifiers in margarine or oleomargarine at 2% (48 FR
52696, Nov. 22, 1983).
Glycerol, a hydrolysis product of mono acylglycerols, is listed by
FDA as a substance generally recognized as safe (GRAS) as a multiple
purpose food additive when used in accordance with good manufacturing
practice (21 CFR 182.1320) and as a GRAS substance when migrating to
food from paper and
[[Page 64257]]
paperboard products (21 CFR 182.90). An exemption from tolerance has
been established by FDA under 21 CFR 182.99 and by EPA under 40 CFR
180.1001(c) and (e) for its use as a solvent and co-solvent in
pesticide formulations and as an adjuvant when added to pesticide
dilutions by growers or applicators prior to application. It is also
deemed GRAS by the Expert Panel of the Flavor and Extract
Manufacturers'Association of America.
Propylene glycol, a hydrolysis product of the propylene glycol
esters, is affirmed as GRAS under 21 CFR 184.1666. It is used as an
anticaking agent, antioxidant, dough strengthener, emulsifier, flavor
agent, formulation aid, humectant, processing aid, solvent and vehicle,
stabilizer and thickener, surface-active agent, and tenderizer in foods
at levels not to exceed current good manufacturing practice. The
approved uses result in maximum levels, as served of 5% in alcoholic
beverages, 24% in confections and frostings, 2.55% in frozen dairy
products, 97% in seasonings and flavoring, 5% in nuts and nut products,
and 2% in all other food categories. Propylene glycol is also exempt
from the requirement of tolerance by EPA under 40 CFR 180.1001(c) and
(e), and has been deemed GRAS by the Expert Panel of the Flavor and
Extract Manufacturers' Association of America.
I. International Tolerances
No international tolerances have been established for the active
ingredients in the VWX-42 Technology system. The FAO and the WHO
through the JECFA has reviewed mono and diacylglycerol and propylene
glycol esters of fatty acids and determined that they may be used
safely in foods at levels of 1-3 grams per day for an adult. It as
observed that ``alterations in the fatty acid distribution or
polyglycerol content of individual members of a group of diverse
substances have no toxicological bearing and only affect the physical
and emulsifying properties of each ester.'' The Committee concluded
safety based upon the biochemical and metabolic evidence that the
breakdown products of such additives are normal dietary constituents.
[FR Doc. 01-30371 Filed 12-11-01; 8:45 am]
BILLING CODE 6560-50-S