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BIOPESTICIDES REGISTRATION ACTION DOCUMENT
Natamycin
PC Code: 051102
U.S. Environmental Protection Agency
Office of Pesticide Programs
Biopesticides and Pollution Prevention Division
May 14, 2012
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TABLE OF CONTENTS
I. EXECUTIVE SUMMARY 4
II. ACTIVE INGREDIENT OVERVIEW 7
III. REGULATORY BACKGROUND 7
A. Classification 7
B. Food Clearances/Tolerances 8
IV. RISK ASSESSMENT 8
A. Active Ingredient Characterization Error! Bookmark not defined.
B. Human Health Assessment 8
C. Environmental Assessment Error! Bookmark not defined.
V. ENVIRONMENTAL JUSTICE Error! Bookmark not defined.
VI. RISK MANAGEMENT AND REGISTRATION DECISIONS 14
A. Determination of Eligibility 14
B. Regulatory Decision 15
C. Labeling 15
VII. ACTIONS REQUIRED OF THE REGISTRANT 16
A. Reporting of Adverse Effects and Hypersensitivity Incidents 16
VIII. GLOSSARY OF ACRONYMS AND ABBREVIATIONS....Error! Bookmark not defined
IX. BIBLIOGRAPHY STUDIES SUBMITTED IN SUPPORT OF THESE
REGISTRATIONS 24
A. Studies Submitted in Support of Natamycin
B. EPA Risk Assessment Memoranda 27
C. References
27
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BIOPESTICIDES REGISTRATION ACTION DOCUMENT TEAM
Office of Pesticide Programs
Biopesticides and Pollution Prevention Division
Biochemical Pesticides Branch (BPB)
Cheryl Greene Regulatory Action Leader
Russell Jones, Ph.D. Lead Science Reviewer/Senior Biologist
Linda Hollis Branch Chief
HEALTH CANADA PEST MANAGEMENT REGULATORY AGENCY
Bing Dang Science Coordination Officer
PMRA, Health Canada
2720 Riverside Drive
Ottawa, ON K1A 0K9
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I. EXECUTIVE SUMMARY
Page 4
Natamycin is a new biochemical pesticide active ingredient intended for use as a fungistat to
control the germination of mold and yeast spores in the growth media of mushrooms produced in
enclosed mushroom production facilities. Natamycin is a naturally-occurring antimycotic
compound derived from the common soil microorganisms, Streptomyces natalensis,
Streptomyces lydicus, and Streptomyces chattanoogensis. It is commercially produced by a
submerged oxygen-based fermentation of Streptomyces natalensis cells which are then lysed by
increasing the temperature in the fermentation vessel thereby causing the release of Natamycin
from the cell solids. . Natamycin was originally discovered in Streptomyces natalensis in South
Africa in the early 1950s, and was subsequently discovered to also occur naturally in North
America in Streptomyces lydicus, and Streptomyces chattanoogensis. Natamycin has a non-toxic
mode of action and functions as a fungistat, preventing the germination of fungal spores. It has
no effects on fungal mycelia. Development of antibiotic resistance to Natamycin has not been
reported during its entire history of use.
Natamycin has been used as a food preservative worldwide for over 40 years (WHO TRS 430)
and is approved as a food additive/preservative by the European Union, the World Health
Organization and individual countries for use as a fungistat to suppress mold on cheese, meats
and sausage. In the United States, Natamycin is approved by The Food and Drug Administration
(FDA) as a direct food additive/ preservative for the inhibition of mold and yeast on the surface
of cheeses (21CFR172.155) and as an additive to the feed and drinking water of broiler chickens
to retard the growth of specific molds (21CFR573.685). Natamycin is also FDA approved for
use as a treatment to suppress fungal eye infections such as blepharitis, conjunctivitis and
keratitis. On August 17, 2007, the EPA's Biochemical Classification Committee classified
Natamycin as a Biochemical Pesticide active ingredient, and -Streptomyces lydicus (the source of
Natamycin) is currently registered by the Agency under Registration Nos. 73314-1, -2, and -4 as
a microbial pesticide for greenhouse, nursery, turfgrass, agricultural, and seed treatment uses.
The Biopesticides and Pollution Prevention Division (BPPD) determined that the
data/information submitted for product chemistry and Tier I acute toxicity for Natamycin satisfy
the current guideline requirements. Acceptable studies were submitted for the subchronic 90-day
oral (OCSPP 870.3100) and 90-day inhalation (OCSPP 870.3465) data requirements. Those data
showed no biologically significant changes in the hematology or clinical chemistry profiles of
the test animals. No 90-Day Dermal (OCSPP 870.3250) or 90-Day Inhalation (OCSPP
870.3465) studies were submitted and none are required since products containing Natamycin
will only be applied in irrigation water to mushrooms growing in enclosed facilities. Based on
this application method, the Agency does not anticipate any repeated dermal exposure to
Natamycin.
In lieu of a Guideline study the applicant developed a science based rationale in support of
Prenatal Developmental Toxicity ((OCSPP 870.3700) for Natamycin. The rationale was
supported with information and data obtained from the open technical literature. The rationale
relies primarily on a comprehensive review of Natamycin by the European Food Safety
Authority (EFSA, 2009) and its associated citations. By way of the EFSA review of Natamycin
(aka Pimaricin), the rationale demonstrated that Natamycin is poorly absorbed by mammals and
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that it does not pose any dietary concerns based on current usage. The Agency concurs with this
conclusion based on per capita consumption of all mushroom commodities in the United States
(USDA/ERS, 2010), dietary intake from treated, unwashed mushrooms is conservatively
estimated to be no more than 0.00030 mg a.i./kg bw/person/day. This value is well below any
known acute oral, subchronic and chronic dietary, reproductive, and developmental endpoints for
Natamycin by many orders of magnitude. In addition, the estimated dietary intake from
unwashed, treated mushrooms also is well below the Acceptable Dietary Intake (ADI) of 0.3
established by Joint FAO/WHO Expert Committee on Food Additives (JECFA, 2001& 2006)
and an ADI of 0.1 established European Food Safety Authority (EFSA, 2009). The information
submitted by the registrant, along with open technical literature also support the Tolerance
Exemption Petition submitted for Natamycin.
Tier I studies were not submitted for non-target organisms and environmental fate data
requirements (OCSPP 850.1010 to 850.4450) for Natamycin and such studies are not required.
Based on its use pattern and use instructions as a fungistat intended solely for use in indoor,
enclosed mushroom production facilities, Natamycin exposure to non-target organisms is not
expected. Further, EPA has determined that Natamycin will have "No Effect" on any currently
listed threatened or endangered species or any designated critical habitat based on its use pattern
and use instructions and the fact that Natamycin is intended solely for indoor use in enclosed
mushroom production facilities.
Based on the acute toxicity data for Natamycin, the active ingredient is toxicity category III.
EPA has not identified any toxic endpoints for nontarget mammals, birds, plants, aquatic, or soil
organisms. EPA has no concerns for any nontarget organisms exposed to Natamycin when used
in accordance with approved label directions. Given that Natamycin has very low toxicity and
presents little, if any, risk to nontarget organisms, EPA has concluded that it is in the best
interests of the public to issue the registration for the Natamycin TGAI (EPA File Symbol No.
87485-1) and the end-use product Natamycin L (EPA File Symbol No. 87485-2), which contain
this new active ingredient, Natamycin.
The Agency has reviewed the data/information in support of the requirements for granting
registration under Section 3(c)(5) of the Federal Insecticide, Fungicide and Rodenticide Act
(FIFRA) and determined that the data/information submitted adequately satisfy current
guideline requirements (see 40 CFR Subpart U § 158.2000).
On October 1, 2009, EPA announced a new policy to provide a more meaningful opportunity for
the public to participate on major registration decisions before they occur. According to this
policy, EPA provides a public comment period prior to making a registration decision for the
following types of applications: new active ingredients, first food use, first outdoor use, first
residential use; and any registration decisions for which the Agency believes there may be
substantial public interest.
Consistent with the policy of making registration actions more transparent, Natamycin was
subject to a 30 day comment period as a "new active ingredient". The notice for this comment
period included the draft Biopesticides Registration Action Document (BRAD) and draft product
labels for the technical grade active ingredient, Natamycin TGAI and the EP, Natamycin L.
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which contain this new active ingredient, Natamycin. The docket identification (ID) number is
EPA-HQ-OPP-2010-0685. The Agency believes that based on the risk assessment and
information submitted in support of the registration of the EP containing Natamycin, it is in the
best interests of the public to issue the registration for Natamycin L. The basis for this decision
can be found in the risk assessment for Natamycin, which is characterized in this BRAD.
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II. ACTIVE INGREDIENT OVERVIEW
Common Name: Natamycin
Chemical Name: IUPAC Chemical Name:
(\R,3S,5R,1R,%E,\2R,\AE,\6E, 18E,20E,22R,24S,25R,26S)-22-[(3-
amino-3,6-dideoxy-P-D-mannopyranosyl)oxy]-l,3,26-trihydroxy-
12-methyl-10-oxo-6,l l,28-trioxatricyclo[22.3.1.05'7]octacosa-
8,14,16,18,20-pentaene-25-carboxylic acid
Trade & Other Names: Natamycin L
Pimaricin
Tennectin
Delvocid
CAS Registry Number: 7681-93-8
OPP Chemical Code: 051102
Type of Pesticide: Fungistat
III. REGULATORY BACKGROUND
On May 20, 2010, EPA received an application filed by Keller and Heckman, 1001 G Street,
N.W., Suite 500 West, Washington, D.C.20001 on behalf of DSM Food Specialties B.V.,
Alexander Fleminglaan 1, Delft, The Netherlands 2613 AX to register the products Natamycin
TGAI (EPA File Symbol No. 87485-1), and Natamycin L (EPA File Symbol No. 87485-2)
containing the new biochemical active ingredient Natamycin. The application was submitted to
both the U.S. Environmental Protection Agency (EPA) and The Health Canada Pest
Management Regulatory Agency (PMRA) along with a request for a North American Free Trade
Agreement (NAFTA) Joint Review of the applications1. Concurrent with these applications,
DSM filed a petition for a tolerance exemption for residues of Natamycin on mushrooms when
used as a fungistat in enclosed mushroom producing facilities. No comments were received
following publication of the notice. On November 24, 2010, EPA published in the Federal
Register (76 FR 22067) a Notice of Receipt (NOR) announcing receipt of the applications and
on April 20, 2011 EPA published in the Federal Register (76 FR 22067) a Notice of Filing
(NOF) announcing receipt of the petition.
A. Classification
1 See http://www.epa.sov/oppfeadl/international/naftatws/suidance/iointreview-biope.pdf.
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Natamycin was classified as a Biochemical Pesticide by the Agency's Classification Committee
on August 17, 2007. The Classification Committee confirmed its nontoxic mode of action, its
natural occurrence in the environment, and its history of exposure to humans and the
environment without known toxicity.
B. Food Clearance/Tolerances
Natamycin is intended for use as a fungistat only on mushrooms grown in enclosed mushroom
growing facilities. The Agency considers this use to be a food use. On April 20, 2011 the
Agency issued a notice in the federal register (76 FR 22067) of the filing of a petition by DSM
for the exemption of residues of on mushrooms.
IV. RISK ASSESSMENT
A. Active Ingredient Characterization
Natamycin is a biochemical active ingredient intended for use as a fungistat to be in enclosed
mushroom production facilities for the control of fungi and mold on mushrooms. It is derived
from the common soil microorganism, Streptomyces natalensis and is commercially produced by
submerged aerobic fermentation by Streptomyces natalensis, Streptomyces lydicus, and
Streptomyces chattanoogensis. Fermentation is conducted for several days, and the antibiotic is
isolated either by broth extraction or by extraction of the mycelium. Dried Natamycin recovered
from the fermentation broth is white to cream-colored and has little or no odor or taste; in the
crystalline form it is very stable. During the extraction procedure the Natamycin is dissolved and
filtered through a membrane. The membrane is not permeable to the organism and the
concentration of the extraction is high enough to kill the organism. None of the microorganism
that is used to produce Natamycin is viable at the end of this process.
All product chemistry and composition data requirements for Natamycin have been satisfied.
The information submitted to support the product chemistry and composition data requirements
for Natamycin are summarized in Tables 1 and 2 in Appendix A.
B. Human Health Assessment
1. Toxicology
For acute toxicity data requirements, toxicity categories are assigned based on the hazard(s)
identified from studies and/or information on file with the Agency. The active ingredient is
classified into Toxicity Category I, II, III or IV where Toxicity Category I indicates the highest
toxicity and Toxicity Category IV indicates the lowest toxicity.
Adequate mammalian toxicology data/information is available to support registration o
Natamycin. All toxicology data requirements for Natamycin have been satisfied.
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a. Acute Toxicity
Acute toxicity testing is required to 1) determine systemic toxicity from acute exposure via the
dermal, inhalation and oral routes, 2) determine irritant effects from exposure to the eyes, and 3)
determine the potential for skin sensitization (allergic contact dermatitis).
Tier I acute toxicity studies submitted and reviewed showed that Natamycin is Toxicity Category
III for acute oral toxicity and Toxicity Category IV for acute dermal toxicity, acute inhalation
toxicity, primary eye irritation, and primary dermal irritation. Natamycin is not a sensitizer.
Natamycin is not a mutagen and is not cytotoxic.
For more information regarding acute toxicity data requirements, refer to Table 3 in Appendix A.
b. Subchronic Toxicity
Subchronic data are required to determine a no-observed-effect-level (NOEL) and any toxic
effects associated with repeated or continuous exposure to a test substance for a period of ninety
days. Subchronic (90-day) dermal toxicity and Subchronic inhalation studies were not
submitted, but are not required based on a lack of repeated exposure to workers and applicators
via these two routes of exposure.
A 90-day oral (OCSPP 870.3100) and 90-day inhalation (OCSPP 870.3465) study was
submitted and is acceptable based on the data demonstrating that no biologically significant
changes in the hematology or clinical chemistry profiles were observed. The Agency concurs
with the findings.
For more information regarding the subchronic data requirements, refer to Table 3 in Appendix
A.
c. Developmental Toxicity and Mutagenicity
In lieu of a Guideline study the applicant developed a science based rationale in support of
Developmental Toxicity ((OCSPP 870.3700) for Natamycin. The rationale was supported with
information and data obtained from the open technical literature. The rationale relies primarily
on a comprehensive review of Natamycin by the European Food Safety Authority (EFSA, 2009)
and its associated citations. By way of the EFSA review of Natamycin (aka Pimaricin), the
rationale demonstrated that Natamycin is poorly absorbed by mammals and that it does not pose
any dietary concerns based on current usage. The Agency concurs with this conclusion based on
per capita consumption of all mushroom commodities in the United States (USDA/ERS, 2010),
dietary intake from treated, unwashed mushrooms is conservatively estimated to be no more than
0.00030 mg a.i./kg bw/person/day. This value is well below any known acute oral, subchronic
and chronic dietary, reproductive, and developmental endpoints for Natamycin by many orders
of magnitude. In addition, the estimated dietary intake from unwashed, treated mushrooms also
is well below the Acceptable Dietary Intake (ADI) of 0.3 established by Joint FAO/WHO Expert
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Committee on Food Additives (JECFA, 2001& 2006) and an ADI of 0.1 established European
Food Safety Authority (EFSA, 2009). The information submitted by the registrant, along with
open technical literature also support the Tolerance Exemption Petition submitted for Natamycin.
For more information regarding developmental toxicity and Mutagenicity data requirements,
refer to Table 3 in Appendix A.
d. Tier II and Tier III (40 CFR § 158.2050)
No Tier II and Tier III studies were required, based on a lack of acute toxicity in the Tier I
studies and a lack of exposure relative to Natamycin's use pattern as a fungistat to control mold
on mushrooms in enclosed mushroom producing facilities.
c. Effects on the Endocrine System
As required under Federal Food, Drug, and Cosmetic Act (FFDCA) section 408(p), EPA has
developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain
substances (including pesticide active and other ingredients) may have an effect in humans or
wildlife similar to an effect produced by a "naturally occurring estrogen, or other such endocrine
effects as the Administrator may designate." The EDSP employs a two-tiered approach to
making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays
to identify the potential of a chemical substance to interact with the estrogen, androgen, or
thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found
to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage
of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on
the available data. Tier 2 testing is designed to identify any adverse endocrine-related effects
caused by the substance, and establish a quantitative relationship between the dose and the E, A,
or T effect.
Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first
group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients.
This list of chemicals was selected based on the potential for human exposure through pathways
such as food and water, residential activity, and certain post-application agricultural scenarios.
This list should not be construed as a list of known or likely endocrine disruptors.
Natamycin is not among the group of 58 pesticide active ingredients on the initial list to be
screened under the EDSP. Under FFDCA section 408(p), EPA must screen all pesticide
chemicals. Accordingly, EPA anticipates issuing future EDSP orders/data call-ins for all
pesticide active ingredients. For further information on the status of the EDSP, the policies and
procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery, please
visit our website: htty://www.eya.gov/endo/.
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2. Dose Response Assessment
Page 11
No definitive toxicological endpoints were identified for Natamycin and no effects were
observed at maximum hazard doses.
3. Dietary Exposure and Risk Characterization
Dietary exposure to Natamycin is expected to be minimal. Natamycin is a fungistat that has a
long history of use in food for the prevention of spoilage. The active ingredient was
demonstrated to be minimally toxic in OCSPP Guideline studies using the TGAI (see Appendix
A, Table 4). In a review of toxicological literature by the European Food Safety Agency (EFSA,
2009), Natamycin was shown to be poorly absorbed by gastrointestinal systems of mammals and
rapidly excreted in the feces (Blankwater and Hespe, 1979; Hespe and Meier, 1980; both
reviewed and cited in EFSA, 2009). In addition, Natamycin is rapidly degraded by stomach
acids, with a 1-hour half-life in simulated gastric juice (Morgenstern and Muskens, 1976;
reviewed and cited in EFSA, 2009).
All inert ingredients used in the end-use product, Natamycin L, are approved for food use under
40 CFR 180.950 and 40 CFR 180.960; and are considered to be Generally Recognized As Safe
(GRAS) by FDA.
Acute and Chronic Dietary Exposure and Risks for Sensitive Subpopulations, Particularly
Infants and Children
Based on the minimal toxicity of Natamycin demonstrated in laboratory testing of the TGAI (see
Table 4), the anticipated minimal dietary exposure, and the mode of action of Natamycin as a
fungistat, acute and chronic dietary risks for sensitive subpopulations are not anticipated.
4. Drinking Water Exposure Risk Characterization
Based on the intended use sites (enclosed mushroom production facilities) and use directions
(steam sterilization of compost and casing prior to disposal outside of the mushroom growth
facility), it is highly unlikely that residues of Natamycin will enter any sources of drinking water.
However, in the unlikely event that Natamycin residues escape from its indoor application site
(completely enclosed mushroom houses), its concentration in surface waters would never exceed
30-50 ppm due to its low solubility in water; up to 50 ppm @ 20-25°C and pH 5-7.5; and at-t
pH 10 it completely degrades (USEPA, 2011). Natamycin is extremely sensitive to
UV light and is completely degraded by UV within 24 hours of exposure in aqueous solution
(Koontz et. al., 2003). Even assuming that no environmental degradation takes place, should
Natamycin be ingested via drinking water, gastric juices typically found in the human stomach
will completely degrade Natamycin within 24 hrs (JECFA, 2006). Finally, the non-definitive
endpoints for acute oral toxicity (>1820 ppm) and subchronic oral toxicity (>500 ppm in the diet)
(USEPA, 2011) are approximately 36X and 10X greater than the highest measured solubility of
Natamycin in water. For these reasons, the Agency believes that there are no concerns for
exposure of humans to Natamycin in drinking water.
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5. Occupational, Residential, School and Day Care Exposure and Risk
Characterization
Based on use sites (enclosed mushroom production facilities) and use directions (steam
sterilization of compost and casing prior to disposal outside of the mushroom growth facility), no
Residential, School, or Day-Care exposure is expected.
a. Occupational Exposure and Risk Characterization
Occupational exposure to mixer/loader/applicators is expected to be minimal, but can be
mitigated with appropriate Personal Protective Equipment (PPE). See Discussion of Human
Activities below.
b. Residential, School and Day Care Exposure and Risk Characterization
A residential, school and day care exposure assessment was not conducted for Natamycin.
However, based on use sites of products containing Natamycin (enclosed mushroom production
facilities) and use directions (steam sterilization of compost and casing prior to disposal outside
of the mushroom growth facility), no Residential, School, or Day-Care exposure is expected.
6. Aggregate Exposure from Multiple Routes Including Dermal, Oral, and
Inhalation
Based on the mode of action of the active ingredient as a fungistat, no aggregate exposure is
anticipated.
7. Cumulative Effects
Based on the mode of action of the active ingredient as a fungistat, minimal dietary exposure
(see Dietary Exposure and Risk Characterization above) and rapid degradation and excretion
from animal systems (EFSA, 2009), no cumulative exposure is anticipated.
Pursuant to FFDCA section 408(b)(2)(D)(v), EPA has considered available information
concerning the cumulative effects of Natamycin residues and other substances that have a
common mechanism of toxicity. These considerations include the potential for cumulative
effects on infants and children of Natamycin residues and other substances with a common
mechanism of toxicity. Because Natamycin has a long history of dietary consumption without
incident, and because the available data show a lack of acute toxicity in the Tier I studies as well
as a lack of exposure relative to Natamycin's use pattern as a fungistat to control mold on
mushrooms in enclosed mushroom producing facilities, the Agency concludes that Natamycin
does not share a common mechanism of toxicity and that there are no potential cumulative
effects arising from incidental exposures to Natamycin residues in or on food commodities.
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8. Risk Characterization
The Agency considered human exposure to Natamycin in light of the standard for registration in
the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the relevant safety factors
in FFDCA. A determination has been made that no unreasonable adverse effects to the U.S.
population in general, and to infants and children in particular, will result from the use of
Natamycin when label instructions are followed.
C. ENVIRONMENTAL ASSESSMENT
1. Ecological Hazards
Tier I studies were not submitted but are not required. However, based on its use pattern and use
instructions as a fungistat intended solely for use in indoor, enclosed mushroom production
facilities, exposure to non-target organisms is not expected. Additionally, based on its use
pattern and use instructions, EPA has determined that Natamycin will have "No Effect" on any
currently listed threatened or endangered species or any designated critical habitat.
For more information regarding nontarget organism toxicity data requirements, please refer to
Table 4 in Appendix A.
2. Environmental Fate and Ground Water Data
Environmental fate and groundwater data are not required at this time because the results of the
nontarget organism toxicity assessment (Tier I data requirements) did not trigger these Tier II
data requirements.
3. Endangered Species Assessment
The Agency has not conducted a risk assessment that supports a complete endangered species
determination. The ecological risk assessment planned during registration review will allow the
Agency to determine whether Natamycin use has "no effect" or "may effect" federally listed
threatened or endangered species (listed species) or their designated critical habitats. When an
assessment concludes that a pesticide's use "may affect" a listed species or its designated critical
habitat, the Agency will consult with the U.S. Fish and Wildlife Service and/or National Marine
Fisheries Services (the Services) as appropriate.
D. EFFICACY DATA
Product performance data must be developed for all pesticides to ensure that pesticide products
will perform as intended and that unnecessary pesticide exposure to the environment will not
occur as a result of the use of ineffective products. The Agency reserves the right to require on a
case-by- case basis, submission of efficacy data for any pesticide product registered or proposed
for registration that are intended to be used to control a pest of significance public health
importance and a public health pest as defined in FIFRA section 28(d) and section 2(nn). For
further guidance on product performance requirement, refer to Pesticide Registration Notice (PR)
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Notices 96-7, 2002-1 and Explanation of Statutory Framework for Risk-Benefit Balancing for
Public Health Pesticides (http://www.epa.gov/PR Notices/prl996-7.pdf)
(http://www.ea.gov/PR Notices/pr2002-1 .pdf) and (http://www.epa.gov/pesticides/health/risk-
benefit.htm).
The EPs submitted with this new active ingredient did not list pests of significance public health
importance or a public health pest as defined in FIFRA section 28(d) and section 2(nn).
Therefore, the Agency does not require product performance for Natamycin under the proposed
uses. However, these data are required by Canada/PMRA and was submitted and reviewed by
Canada/PMRA as part of the joint review of the active ingredient. We are reporting the results of
that review below.
Canada/PMRA Review
Natamycin has proven to be an extremely effective in food preservation because its mode of
action is to stop the growth of molds and yeasts before damage begins. Curative fungicidal
treatments cannot always negate the harmful effects that a growing mycelium leaves behind. In
addition, fungi can produce dangerous mycotoxins, some of which are even carcinogenic, that
can cause health problems. Removing the fungi has no effect on mycotoxins once they are
embedded. Natamycin is able to protect food products against mold growth for long periods of
time due to its stability and crystalline form. It has a low level of solubility in water (-50 ppm)
and in organic materials. Specifically, Natamycin can reduce the development of Verticillium
disease - a use for which this active ingredient is being registered - of the commercial mushroom.
As a fungistat to control Verticillium disease, the best control was noted when 2 mL (form) per
sq m were applied. There appears to be little difference between 2 applications (pinning and
casing) or 4 applications (pinning, casing, between 1st and 2nd breaks and between 2nd and 3rd
breaks). All product performance data required by Canada/PMRA for registration of Natamycin
have been satisfied.
V. Environmental Justice
EPA seeks to achieve environmental justice, the fair treatment and meaningful involvement of all
people, regardless of race, color, national origin, or income, in the development, implementation,
and enforcement of environmental laws, regulations, and policies. To help address potential
environmental justice issues, the Agency seeks information on any groups or segments of the
population who, as a result of their location, cultural practices, or other factors, may have
atypical, unusually high exposure to Natamycin, compared to the general population. Please
comment if you are aware of any sub-populations that may have atypical, unusually high
exposure compared to the general population.
VI. Risk Management and Registration Decision
A. Determination of Eligibility
Section 3(c)(5) of FIFRA provides for the registration of new active ingredients if it is
determined that (A) its composition is such as to warrant the proposed claims for it; (B) its
labeling and other materials required to be submitted comply with the requirements of FIFRA;
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(C) it will perform its intended function without unreasonable adverse effects on the
environment; and (D) when used in accordance with widespread and commonly recognized
practice, it will not generally cause unreasonable adverse effects on the environment.
The four criteria of the Eligibility Determination for Pesticidal Active Ingredients are satisfied by
the science assessments supporting products containing Natamycin. Such products are not
expected to cause unreasonable adverse effects and are likely to provide protection as claimed
when used according to label instructions. Therefore, EPA concludes that Natamycin is eligible
for registration for the labeled uses.
B. Regulatory Decision
On October 1, 2009, the EPA announced a new policy to provide a more meaningful opportunity
for the public to participate in major registration decisions before they occur. According to this
policy, EPA intends to provide a public comment period prior to making a registration decision
for, at minimum, the following types of applications: new active ingredients; first food uses; first
outdoor uses; first residential uses; or any other registration actions for which EPA believes there
may be significant public interest. Accordingly, this pesticide was subjected to a 30-day
comment period as a new active ingredient with outdoor uses.
The Agency believes that the data submitted fulfill the requirements of registration for products
containing Natamycin for use as a fungistat for use on mushrooms in enclosed mushroom
production facilities. Acute toxicity data for Natamycin demonstrate that it is toxicity category
III and IV for all routes of exposure. (No toxicological endpoints were established.) Data confirm
that Natamycin does not demonstrate subchronic or developmental toxicity, and it is not
mutagenic or genotoxic. EPA has no concerns for any nontarget organisms exposed to
Natamycin in accordance with its approved uses. EPA has not identified any toxic endpoints for
nontarget mammals, birds, plants, aquatic, or soil organisms. Nor are there any anticipated
concerns for any threatened and endangered species. Given the nontoxic character of Natamycin
and because all applicable data requirements have been fulfilled, EPA supports its registration
under FIFRA section 3(c)(5).
C. Labeling
Before releasing pesticide products containing Natamycin for shipment, the applicant is required
to provide appropriate labels. Such labeling for the technical grade active ingredient (TGAI)
must include personal protection equipment (PPE) requirements as follows:
"Mixer/loader/applicators are required to wear the following Personal Protection Equipment
(PPE):
• eye protection
• long pants
• long-sleeved shirt
• closed shoes
• gloves
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Natamycin
Biopesticides Registration Action Document
Page 16
VII. ACTIONS REQUIRED OF THE REGISTRANT
The Agency evaluated the data submitted in connection with the initial registration of Natamycin
and determined that these data fulfill current registration guideline requirements. No additional
data are required to be submitted to the Agency at this time. Additional data may be required for
new uses and/or changes to existing uses.
Notwithstanding the information stated in the previous paragraph, it should be clearly understood
that certain, specific data are required to be reported to the Agency as a requirement for
maintaining the Federal registration for a pesticide product. A brief summary of these types of
data are listed below.
A. Reporting of Adverse Effects and Hypersensitivity Incidents
Reports of all incidents of adverse effects to the environment must be submitted to the Agency
under the provisions stated in FIFRA section 6(a)(2).
Additionally, all incidents of hypersensitivity (including both suspected and confirmed incidents)
must be reported to the Agency under the provisions of 40 CFR § 158.2050(e).
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Natamycin
Biopesticides Registration Action Document
VIII. GLOSSARY OF ACRONYMS AND ABBREVIATIONS
Page 17
ADI average daily intake
BPB Biochemical Pesticides Branch
BRAD Biopesticides Registration Action Document
CA chromosomal aberrations
CAS Chemical Abstracts Service
CFR Code of Federal Regulations
EDSP Endocrine Disruptor Screening Program
EP End-use Product
EPA United States Environmental Protection Agency (Agency)
FDA United States Food and Drug Administration
FFDCA Federal Food, Drug, and Cosmetic Act
FIFRA Federal Insecticide, Fungicide, and Rodenticide Act
FR Federal Register
g gram
g/mL gram per milliliter
Hg mercury
HSDB Hazardous Substances Data Bank
LC50 median lethal concentration. A statistically derived concentration of a
substance that can be expected to cause death in 50% of test animals. It is
usually expressed as the weight of substance per weight or volume of water,
air or feed (e.g., mg/L, mg/kg, or ppm).
LD50 median lethal dose. A statistically derived single dose that can be expected
to cause death in 50% of the test animals when administered by the route
indicated (oral, dermal, or inhalation). It is expressed as a weight of
substance per unit weight of animal (e.g., mg/kg).
LOC level of concern
LOEL lowest observed effect level
[j,g microgram
[j,m micrometer
MRID No. Master Record Identification Number
mg/kg milligram per kilogram
mg/L milligram per liter
mg/ml milligram per milliliter
ml milliliter
mm millimeter
MP Manufacturing-use Product
nm nanometer
NOAEL no observed adverse effect level
NOEC no observed effect concentration
NOEL no observed effect level
OCSPP Office of Chemical Safety and Pollution Prevention
OPP Office of Pesticide Programs
Pa pascal
PC Code Pesticide Chemical Code
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Natamycin Page 18
Biopesticides Registration Action Document
ppb parts per billion
PPE personal protective equipment
ppm parts per million
RQ risk quotient
SCE sister chromatid exchange
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Natamycin Page 19
Biopesticides Registration Action Document
IX. Appendix A. Data Requirements (40 CFR Part 158-Subpart U)
*NOTE: Master Record Identification (MRID) numbers listed in the following tables are
representative of supporting data/information for the original registration of the product
containing this active ingredient. Subsequent to this registration, there may be additional MRIDs
that support registration of other products containing this active ingredient.
TABLE 1. Product Chemistry Data Requirements for Natamycin Technical (40 CFR §
158.2030)
OSCPP
Guideline No.
Study
Results
MRID No.
880.1100
880.1200
880.1400
Product identity;
Manufacturing process;
Discussion of formation
of impurities
Submitted data satisfy
the requirements for
product identity,
manufacturing process,
and discussion of
formation of impurities.
48105401
48105501
47206713
47760931
830.1700
Analysis of samples
Submitted data satisfy
the requirements for
analysis of samples.
48105502
830.1750
Certification of limits
Limits listed in the
confidential statement of
formula are acceptable
48105402
830.1800
Analytical method
Acceptable
48105403
TABLE 2. Physical and Chemical Properties of Natamycin Technical (40 CFR § 158.2030)
OCSPP
Guideline
No.
Property
Description of Results
MRID
830.6302
Color
Colourless
48105503
830.6303
Physical State
Viscous liquid
48105503
830.6304
Odor
Odorless
48105503
830.6313
Stability to Normal
and Elevated
Temperatures,
Metals and Metal
Ions
Natamycin was found stable at
54°C for 14 days. Storage
stability studies supporting
pharmaceutical uses found
acceptable stability in tests of 2
to 5 years in duration.
Natamycin is degraded by
contact with most metals and
metal ions. However, the product
is never packaged in metal
48105504
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Natamycin Page 20
Biopesticides Registration Action Document
TABLE 2. Physical and Chemical Properties of Natamycin Technical (40 CFR § 158.2030)
OCSPP
Guideline
No.
Property
Description of Results
mrii)
containers.
830.6315
Flammability
Does not contain any flammable
components. Consists of - 80%
water.
48105503
830.6317
Storage Stability
The product is stable when
stored for 12 and 18 months in
HDPE plastic bottles at 25°C.
8105405
48439301
48544501
830.6320
Corrosion
Characteristics
The product is not corrosive.
48105405
48439301
48544501
830.7000
pH
6.5 (1% aqueous solution)
6.5 (1% aqueous solution). May
vary between 5 to 7.5
48105503?
830.7100
Viscosity
-2200 mPa.s, Brookfield Test
Method:
RPM-20, Axe=3, T=20°C.
48105503
830.7220
Boiling Point/Range
N/A The product is a solid.
48105503
830.7300
Density
Loose bulk density 0.3 g/mL
Tapped bulk density 0.59 g/mL
830.7560
830.7570
Octanol/water
partition coefficient
(Kow)
Log Kow = -3.67
48105503
830.7840
Water Solubility
30-50 ppm @ 20-25°C and pH
5-
7.5; very soluble at pH> 10 or
pH < 2 but rapidly degrades.
8105503
830.7950
Vapor Pressure
NA The product is a solid
48105503
Formulation Type
Suspension (SU)
48105501
Container Material
and Description
HDPE plastic bucket, jerry can,
drum or jumbo container (5 to
1000 Litres)
48105501
830.7000
pH
6.5 (1% aqueous solution)
6.5 (1% aqueous solution). May
vary between 5 to 7.5
48105503
830.6314
Oxidizing or
Reducing Action
Not applicable. Does not contain
oxidizing or reducing chemicals.
48105503
830.6316
Explodability
Not applicable. Does not contain
any substance capable of
48105503
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Natamycin Page 21
Biopesticides Registration Action Document
TABLE 2. Physical and Chemical Properties of Natamycin Technical (40 CFR § 158.2030)
OCSPP
Guideline
Property
Description of Results
mrii)
No.
exploding.
830.6319
Miscibility
Not formulated to be mixed with
petroleum solvents.
48105503
830.6321
Dielectric
Breakdown Voltage
Not applicable. Not intended to
be used around electrical
equipment.
48105503
1 A = Acceptab
For example,
e; N = Unacceptable (see Deficiency); N/A = Not applicable,
'brown" for 830.6302; "1.021" for 830.7300.
There was a slight shift in the retention time (close to a minute) for the active ingredient based
on the chromatograms provided for the 18-month storage stability study. The applicant provided
a rationale indicating that there was a change in the column packing material (new batch). The
applicant provided additional chromatograms for the controls (standard sample) for the 6- and
18-month to confirm the slight shift in the retention times for the active. The rationale is
accepted.
Table 4. Acute Toxicity Data for the Technical Grade Active Ingredient Product. Natamycin
TGAI (91.02% a.i.):
EPA File Symbol No. 87485-U
Study Tvoe/OCSPP Guideline
LDsn/LCsn/Results
Toxicity
Category
MRU)
Acute Oral Toxicity/OCSPP 870.1100
>2000 mg/kg
(>1820 mg a.i./kg)
ACCEPTABLE
III
48105505
Acute Dermal Toxicity/OCSPP
870.1200
>5050 mg/kg
(>4696.5 mg
a.i./kg)
ACCEPTABLE
IV
48105506
Acute Inhalation Toxicity/OCSPP
870.1300
>2.39 mg/L
(2.18 mg a.i./L)
IV
48105507
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Natamycin Page 22
Biopesticides Registration Action Document
Table 4. Acute Toxicity l):il:i lor (lie Technical Grade Active 1 n«rctlicnl Product. Natamycin
TGAI (91.02% a.i.):
EPA MIc Symbol No. 87485-U
Study Tvoe/OCSPP Guideline
LDsri/LCsn/Results
Toxicity
Category
MRU)
ACCEPTABLE
Primary Eye Irritation/OCSPP
870.2400
No corneal or
positive irritation
effects at 24-hr
post instillation
ACCEPTABLE
IV
48105508
Primary Dermal Irritation/OCSPP
870.2500
PII = 0.1
ACCEPTABLE
IV
48105509
Skin Sensitization-LLNA/OCSPP
870.2600
LLNA SI <3
ACCEPTABLE1
Not a sensitizer
48105510
TABLE 3a. Natamycin residues in mushrooms from the first break (MRID 48105408)
Treatment
Treatment date
Sampling
Tray no.
Residue (mg/kg)
date
Delvocid
At casing, January 26
February 11
29
0.0590
2 lnL/in^
At pinning, February 2
29
0.0890
30
0.0267
30
0.0285
31
0.0287
31
0.0178
32
0.0180
32
0.0192
1
0.0230
1
0.0221
2
0.0369
2
<0.01
3
0.0271
3
0.0344
4
0.0340
4
0.0274
Untreated
NA
February 11
9
<0.01
control
9
<0.01
10
<0.01
10
<0.01
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Natamycin Page 23
Biopesticides Registration Action Document
TABLE 3b. Natamycin residues in washed and unwashed mushrooms from the second and
third breaks (treated three or four times, respectively) MRID 48105408
Treatment
Treatment date
Sampling
date
Tray
no.
Residue
(mg/kg)
Delvocid
2 mL/m^,
unwashed
At casing, January 26
At pinning, February 2
Between breaks 1 & 2,
February 13
February 17
1
0.2370
1
0.1420
At casing, January 26
At pinning, February 2
Between breaks 1 & 2,
February 13
Between breaks 2 & 3,
February 20
February 25
1
0.0407
1
0.1452
Delvocid
2 mL/m^, washed
At casing, January 26
At pinning, February 2
Between breaks 1 & 2,
February 13
February 17
1
<0.01
1
0.0755
At casing, January 26
At pinning, February 2
Between breaks 1 & 2,
February 13
Between breaks 2 & 3,
February 20
February 25
1
0.0123
1
0.0220
Untreated control
NA
February 17
10
<0.01
February 25
10
<0.01
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Natamycin
Biopesticides Registration Action Document
X. BIBLIOGRAPHY
Page 24
MRU)
( ilnlion Uol'orciUT
59399 American Cyanamid Company (1959) Antibiotic A-5283, Myprozine: Acute
Toxicity to Rats; Subacute Toxicity to Rats and Dogs: Re- port No. 59-4.
(Unpublished study received on unknown date un- der unknown admin, no.;
CDL:223651-A)
59400 American Cyanamid Company (1963) Pimaricin (MyprozineA(R)I): Report on Two-
Year Toxicity Studies. Summary of studies 223651-C through 223651-H.
(Unpublished study received on unknown date under unknown admin, no.;
CDL:223651-B)
59401 American Cyanamid Company (1963) Pimaricin: Two-Year Feeding to Dogs: Report
No. 63-6. (Unpublished study received on unknown date under unknown admin, no.;
CDL:223651-C)
59402 American Cyanamid Company (1963) Pimaricin: Two-Year Feeding to Rats: Report
No. 63-7. (Unpublished study, including report no. 63-8, received on unknown date
under unknown admin, no.; CDL: 223651-D)
59403 Levinskas, G.J.; Bushey, C.; Kunde, M.L.; et al. (1963) Pimaricin: Successive
Generation Studies: Report No. 63-9. (Unpublished study received on unknown date
under unknown admin, no.; submit- ted by American Cyanamid Co., Princeton, N. J.;
CDL:223651-E)
59404 Shirk, R.J.; Lovesky, R.L. (1963) A Gross Examination of the Fecal Flora of Rats
Sustained for Two Years on Diets Containing from 0 to 1000 ppm. Pimaricin: Report
FS 3. Progress rept., Jun 21, 1962 to Aug 1, 1962. (Unpublished study received on
unknown date under unknown admin, no.; submitted by American Cyanamid Co.,
Princeton, N.J.; CDL:223651-F)
59405 Shirk, R.J. (1963) The Fecal Excretion and Non-absorption of Pimaricin in Animals:
Report FS 3. Progress rept. (Unpublished study received on unknown date under
unknown admin, no.; submit- ted by American Cyanamid Co., Princeton, N.J.;
CDL:223651-G)
48105400 DSM Food Specialties B.V. (2010) Submission of Product Chemistry, Residue,
Toxicity, and Exposure and Risk Data in Support of the Application for Registration
of Natamycin L and the Petition for Tolerance of Natamycin for Use on Mushrooms.
Transmittal of 11 Studies.
48105401 van der Lee, J.; Jovanovich, A. (2010) Natamycin L: Product Identity, Composition,
and Formulation. Unpublished study prepared by Keller and Heckman LLP. 48 p.
48105402 van der Lee, J.; Jovanovich, A. (2010) Natamycin L: Certified Limits. Unpublished
study prepared by Keller and Heckman LLP. 9 p.
48105403 van Hilten, P. (2010) Natamycin L: Enforcement Analytical Method. Unpublished
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Natamycin Page 25
Biopesticides Registration Action Document
MUII) ( ilnlion Uol'orciUT
study prepared by Keller and Heckman LLP. 18 p.
48105404 van der Lee, J.; Jovanovich, A. (2010) Natamycin L: Summary of Physical/Chemical
Properties and Self-Certification. Unpublished study prepared by Keller and
Heckman LLP. 32 p.
48105405 van der Lee, J.; Jovanovich, A. (201 l)(Sic) Natamycin L: Interim Report for Storage
Stability and Corrosion Characteristics. Project Number: STAB/SLD/09/008.
Unpublished study prepared by DSM Food Specialties B.V. 24 p.
48105406 Jovanovich, A. (2010) Residue Data: Chemical Identity and Directions for Use for
Natamycin L. Unpublished study prepared by Keller and Heckman LLP. 9 p.
48105407 Marin, J. (2010) Development and Validation of an Analytical Method for the
Determination of Natamycin in Mushrooms and Mushroom Compost, Casing and
Casing plus Innoculum. Project Number: 1869W. Unpublished study prepared by
PTRL West, Inc. 73 p.
48105408 Marin, J. (2009) Magnitude of the Residue of Natamycin in Mushrooms. Project
Number: 1915W. Unpublished study prepared by PTRL West, Inc. 165 p.
48105409 Wilms, L.; Jovanovich, A. (2010) Natamycin L: Request for Waiver of 5 Acute
Toxicity Tests. Unpublished study prepared by Keller and Heckman LLP. 16 p.
48105410 Kuhn, J. (2009) Natamycin Liquid Formulation: Acute Eye Irritation Study in
Rabbits: Final Report. Project Number: 12753/09. Unpublished study prepared by
Stillmeadow, Inc. 20 p.
48105411 Wach, M. (2010) Natamycin L: Descriptions of Human Activity for Natamycin L.
Unpublished study prepared by Keller and Heckman LLP. 10 p.
48105500 DSM Food Specialties B. V. (2010) Submission of Product Chemistry and Toxicity
Data in Support of the Application for Registration of Natamycin TGAI and the
Petition for Tolerance of Natamycin for Use on Mushroom. Transmittal of 14
Studies.
48105501 Zuur, P.; Hee, P.; Roghoenath, D.; et al. (2010) Natamycin TGAI: Product Identity,
Composition, and Production. Unpublished study prepared by Keller and Heckman
LLP. 252 p.
48105502 Zeeman, M.; Boogers, I.; Van der Lee, J.; et al. (2010) Natamycin TGAI: Preliminary
Analysis and Certified Limits. Unpublished study prepared by Keller and Heckman
LLP. 140 p.
48105503 Van der Lee, J.; Jovanovich, A. (2010) Natamycin TGAI: Physical and Chemical
Properties. Unpublished study prepared by Keller and Heckman LLP. 9 p.
48105504 Van der Lee, J.; Jovanovich, A. (2010) Stability to Normal and Elevated
Temperatures, Metals, and Metals Ions. Unpublished study prepared by Keller and
Heckman LLP. 27 p.
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Natamycin
Biopesticides Registration Action Document
MRU)
Page 26
Cilsilion Uol'orciUT
48105505 Kuhn, J. (2008) Natamycin TGAI: Acute Oral Toxicity Study (UDP) in Rats: Final
Report. Project Number: 11403/07. Unpublished study prepared by Stillmeadow, Inc.
12 p.
48105506 Kuhn, J. (2008) Natamycin TGAI: Acute Dermal Toxicity Study in Rat: Final
Report. Project Number: 11404/07. Unpublished study prepared by Stillmeadow, Inc.
13 p.
48105507 Crutchfield, V. (2008) Natamycin TGAI: Acute Inhalation Toxicity Study in Rats:
Final Report. Project Number: 11405/07. Unpublished study prepared by
Stillmeadow, Inc. 19 p.
48105508 Kuhn, J. (2008) Natamycin TGAI: Acute Eye Irritation Study in Rabbits: Final
Report. Project Number: 11406/07. Unpublished study prepared by Stillmeadow, Inc.
18 p.
48105509 Kuhn, J. (2008) Natamycin TGAI: Acute Dermal Irritation Study in Rabbits: Final
Report. Project Number: 11407/07. Unpublished study prepared by Stillmeadow, Inc.
13 p.
48105510 Kuhn, J. (2008) Natamycin TGAI: Skin Sensitization: Local Lymph Node Assay in
Mice: Final Report. Project Number: 11408/07. Unpublished study prepared by
Stillmeadow, Inc. 13 p.
48105511 Otterdijk, F. (2003) Natamycin TGAI: 90 Day Oral Toxicity Study with Natamycin
in the Rat. Project Number: NOTOX/PROJECT/339323, 002019. Unpublished study
prepared by Notox B. V. 220 p.
48105512 Knickerbocker, M. (1979) Natamycin TGAI: Teratologic Evaluation of Pimaricin in
Dutch-Belted Rabbits. Project Number: 5906. Unpublished study prepared by Food
& Drug Research Laboratories, Inc. 290 p.
48105513 Verspeek, C. (2002) Natamycin TGAI: Evaluation of the Mutagenic Activity of
Natamycin in the Salmonella typhimurium Reverse Mutation Assay and the
Escherichia coli Reverse Mutation Assay (with Independent Rat). Project Number:
NOTOX/PROJECT/339345. Unpublished study prepared by Notox B.V. 29 p.
48105514 Meerts, I. (2002) Natamycin TGAI: Evaluation of the Ability of Natamycin to Induce
Chromosome Aberrations in Cultured Peripheral Human Lymphocytes. Project
Number: NOTOX/PROJECT/339356. Unpublished study prepared by Notox B.V. 28
P-
48439300 DSM Food Specialties (2011) Submission of Product Chemistry Data in Support of
the Application for Registration of Natamycin L. Transmittal of 1 Study.
48439301 van der Lee, J.; Jovanovich, A. (2011) 12-Month Interim Report for Storage Stability
and Corrosion Characteristics: Natamycin L. Project Number: STAB/SLD/09/008.
Unpublished study prepared by DSM Food Specialties B.V. 38 p.
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Natamycin
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MRU)
Page 27
Citation Reference
48544501 van der Lee, J.; Jovanovich, A. (2011) 18-Month Final Report for Storage Stability
and Corrosion Characteristics: Natamycin L. Project Number: STAB/SLD/09/008.
Unpublished study prepared by DSM Food Specialties B.V. 41p.
48593401 Cox, G.; Bailey, D. (1973) Natamycin TGAI Rat Development Toxicity Study.
Project Number: 1052. Unpublished study prepared by Food & Drug Research
Laboratories, Inc. 495p.
48613501 Thate, C.; Jovanovich, A. (2011) Natamycin TGAI: Request for Waiver of
Teratology Study Data Requirement. Unpublished study prepared by Keller and
Heckman LLP and DSM Food Specialities. 177p.
B. EPA Risk Assessment Memoranda
U.S. EPA. 2010- Jones, Russell, Science Review in Support of Natamycin Technical, Containing
91.02% Natamycin as Its Active Ingredient. Memorandum dated 10/15/2010
201 la. Jones, Russell, Science Review in Support of Natamycin Technical, Containing 91.02%
Natamycin as Its Active Ingredient. Memorandum dated 04/04/2011
U.S. EPA. 201 lb. Jones, Russell, Science Review in Support of Natamycin Technical,
Containing 91.02%) Natamycin as Its Active Ingredient. Memorandum dated 07/11/2011.
U.S. EPA. 201 lc. Jones, Russell, Science Review in Support of Natamycin Technical,
Containing 91.02%) Natamycin as Its Active Ingredient. Memorandum dated 12/13/2011
06/16/2011.
C. References
Joint FAO/WHO Expert Committee on Food Additives (JECFA). 2001. Safety Evaluation of
Certain Food Additives and Contaminants. Natamycin (Pimaricin). WHO Food Additives
Series: 48 http://www.inchem.org/documents/iecfa/iecmono/v48ie06.htm
Joint FAO/WHO Expert Committee on Food Additives (JECFA). 2006. Summary and
Conclusions. Sixty-Seventh Meeting. Rome, 20-29 June 2006.
ftp://ftp.fao.org/ag/agn/iecfa/iecfa67 final.pdf (Accessed 04/04/2011)
European Food Safety Authority (EFSA). 2009. Scientific opinion on the use of Natamycin (E
235) as a food additive. EFSA Panel of Food Additives and Nutrient Sources added to Food
(ANS). EFSA Journal 7(12): 1412, 25 p. http://www.efsa.europa.eu/en/efsaiournal/doc/1412.pdf
(Accessed 04/04/2011)
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Biopesticides Registration Action Document
USDA/ERS. 2010. Mushrooms: Supply and Utilization and Per Capita Consumption.
February 2010 Update, www.ers.usda.gov/data/foodconsumption/spreadsheets/mushroom.xls
(Accessed 04/04/2011).
World Health Organization (WHO). 2009. The WHO Recommended Classification of
Pesticides by Hazard and Guidelines to Classification.
Joint FAO/WHO Expert Committee on Food Additives (JECFA). 1968, 1976, 2002, 2006, and
2007. See EFSA 2009 for specific reference citations.
European Food Safety Authority (EFSA). 2009. Scientific opinion on the use of Natamycin (E
235) as a food additive. EFSA Panel of Food Additives and Nutrient Sources added to Food
(ANS). EFSA Journal 7(12): 1412, 25 p. http://www.efsa.europa.eu/en/efsaiournal/doc/1412.pdf
(Accessed 04/04/2011)
USDA/ERS. 2010. Mushrooms: Supply and Utilization and Per Capita Consumption.
February 2010 Update, www.ers.usda.gov/data/foodconsumption/spreadsheets/mushroom.xls
(Accessed 04/04/2011).
REFERENCES CITED BY EFSA (2009).
Blankwater, Y. J. and W. Hespe. 1979. Autoradiographic and bioautographic study of the
distribution of oral Natamycin in the rat. Unpublished report No. 20.502, dated 8 May 1979
from Gist-Brocdades NV, Delft.
Cox, G. E., D. E. Bailey, and K. Morgareidge. 1973. Multigeneration studies in rats with
Delvocid brand of Pimaricin. Unpublished report No. 1-1052 submitted to WHO by Food and
Drug Research Laboratories, Inc.
Hespe, W. and A. M. Meier. 1980. Studies involving in regard to the resorption of radioactivity
following the oral administration of 14C-pimaricin, applied on cheese, in comparison to other
oral forms of administration. Unpublished report No. 20.532, dated 4 February 1980, submitted
to WHO by Gist-Brocades NV, Haarlem.
Hutchinson, E. B., W. E. Ribelin, and G. J. Levinskas. 1966. Report on acid-degraded
Pimaricin: Ninety-eight day repeated feeding to rats. Unpublished report submitted to WHO by
American Cyanamid Co., Central Medical Department.
Levinskas, G. J., C. B. Shaffer, C. Bushey, M. L. Kunde, D. W. Stackhouse, L. B. Vidone, B.
Javier, and E. Monell. 1963. Two year feeding study in rats. Unpublished report from the
Central Medical department. Submitted to WHO by American Cyanamid Co.
Levinskas, G. J., W. E. Ribelin, and C. B. Shaffer. 1966. Acute and chronic toxicity of
Pimaricin. Toxicology and Applied Pharmacology 8: 97-109.
Morgenstern, A. P. and G. J. A. M. Muskens. 1976. Further data on the toxicity of the
decomposition products of Pimaricin. Unpublished report Gist-Brocades NV, Delft, 4 pages.
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Page 29
Pacifici, G. M. and R. Nottoli. 1995. Placental transfer of drugs administered to the mother.
Clinical Pharmacokinetics 28(3): 235-269.
Van Ecken, C. J., R. D. R. Birtwhistle, and M. J. e. Aboulwafa-wan Velthoven. 1984. Three
months study in dogs of the toxicity of Natamycin by addition to the food. Unpublished report
12.401, 24 October 1984. Submitted to WHO by Gist-Brocades Research and Development.
J
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