United States Prevention, Pesticides EPA738-R-96-025
Environmental Protection And Toxic Substances September 1996
Agency (7508W)
&EPA ReregisJtratiojn
Eligibility Decision (RED)
Chlorhexidine
diacetate 738R96025
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United States
Environmental Protection
Agency
Prevention, Pesticides
And Toxic Substances
(7508W)
EPA-738-F-96-025
September 1996
&EPA R.E.D. FACTS
Chlorhexidine
diacetate
Pesticide
Reregistration
Use Profile
Regulatory
History
All pesticides sold or distributed in the United States must be registered by
EPA, based on scientific studies showing that they can be used without
posing unreasonable risks to people or the environment. Because of
advances in scientific knowledge, the law requires that pesticides which
were first registered years ago be reregistered to ensure that they meet
today's more stringent standards.
In evaluating pesticides for reregi strati on, EPA obtains and reviews a
complete set of studies from pesticide producers, describing the human
health and environmental effects of each pesticide. The Agency imposes
any regulatory controls that are needed to effectively manage each
pesticide's risks. EPA then reregisters pesticides that can be used without
posing unreasonable risks to human health or the environment.
When a pesticide is eligible for reregi strati on, EPA explains the basis
for its decision in a Reregistration Eligibility Decision (RED) document
This fact sheet summarizes the information in the RED document for
reregi strati on case 3038, chlorhexidine diacetate.
Chlorhexidine diacetate is a disinfectant used to control bacteria on
agricultural premises, egg handling and packing equipment, and meat and
poultry processing plants, and certain viruses in veterinary settings.
End-use products contain 2% of the active ingredient and are
formulated as soluble concentrates or liquids.
Chlorhexidine diacetate is applied by open-pour loading of liquid
formulations, hand-wiping surfaces, dipping tools/implements into diluted
disinfectant solution, mopping of surfaces, using hand-held high- and low-
pressure spray equipment, and with fogging devices. Use practice
limitations prevent exposure to food items.
Products formulated with chlorhexidine diacetate as an active
ingredient were first registered in the U.S. as early as 1955 for use as a farm
premise disinfectant/virucide
Currently, two products (each containing 2% chlorhexidine diacetate)
are registered for use as hard surface-treatment disinfectants/virucides.
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Human Health Toxicity
Assessment In acute toxicity studies using laboratory animals, the Agency
concluded that chlorhexidine diacetate is mildly to moderately toxic when
administered by inhalation, oral and dermal routes. However, in repeat
primary eye irritation studies, the chemical is severely toxic.
In a subchronic dermal rabbit toxicity study systemic effects included
degenerative changes in the livers of females. In a developmental toxicity
study in rats, no observable malformations nor signs of developmental
toxicity were found at any dose level tested. A battery of mutagenicity
studies were negative for mutagenic effects.
Dietary Exposure
Chlorhexidine diacetate is registered for use on processing surfaces in
federally inspected meat, poultry, egg, and rabbit processing plants as a
disinfectant. The labeling for these products directs the user to remove or
carefully cover the food products prior to application, and to use a potable
water rinse after treatment. The U.S. Department of Agriculture and the
EPA have determined that disinfectants, when applied to federally
inspected meat, poultry, egg, and rabbit processing plants as described
above, do not present dietary exposure risks (USDA, FSIS publication
#1419, "List of Proprietary Substances and Nonfood Compounds").
Occupational and Residential Exposure
Based on current use patterns, handlers (mixers, loaders, and
applicators) may be exposed to chlorhexidine diacetate during and after
normal use of products containing this active ingredient. An exposure
assessment is appropriate because of the toxicological endpoint from the
subchronic dermal study.
Several exposure scenarios are possible, including open pouring,
wiping, dipping of implements, mopping, spraying, and fogging. Data are
not available to calculate exposures for the fogging scenario. For the
remaining scenarios, EPA's exposure assessment, which considered
combined dermal and inhalation exposures, suggests that short- and
intermediate-term exposures are greatest for the open pouring scenario
while chronic exposures are greatest from wiping activities. However, the
calculated margins of exposure (MOEs) for these uses were greater than
100. MOEs of greater than 100 are considered acceptable.
Because the exposure data used to calculate these risks were
generated for workers wearing personal protective equipment (PPE), these
PPE are required as described in the product labeling section of this fact
sheet.
The potential for exposures to chlorhexidine diacetate exists following
application. However, the Agency believes that exposures from post-
application are significantly lower than exposures during application,
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provided entry into treated areas is restricted immediately following
application. The Agency is concerned for workers exposed to
chlorhexidine diacetate from their entry into the fogged area. To protect
these workers, PPE, including gloves and a respirator, is required.
Human Risk Assessment
Chlorhexidine diacetate generally is of low to moderate acute toxicity,
but is highly acutely toxic when applied to the eye. It causes liver effects in
animal studies.
The Agency is concerned for risks posed to chlorhexidine diacetate
handlers and workers reentering areas recently treated with the pesticide.
To mitigate these risks, PPE is established for both handlers and workers
in early-entry situations.
Environmental For chlorhexidine diacetate, like other pesticides whose uses are
Assessment limited to indoor sites, the Agency required a limited set of ecotoxicology
and environmental fate studies. The Agency does not routinely conduct full
environmental assessments on such pesticides since minimal to no
environmental exposure is expected from the indoor use patterns. Only a
limited set of studies are necessary to characterize the pesticide's hazard
potential in the case of unanticipated environmental exposures caused by
transportation accidents, spills, or improper disposal or use.
Ecological Effects
Chlorhexidine diacetate is slightly toxic to avian species on an acute
and subacute oral dietary basis, moderately to highly toxic to fish, and very
highly toxic to aquatic invertebrates. Current uses of chlorhexidine
diacetate are expected to result in minimal exposure or risk to the
environment. Therefore, no environmental risk mitigation measures are
imposed at this time.
Additional Data The Agency is requiring product-specific data including product
Required chemistry and acute toxicity studies, revised Confidential Statements of
Formula (CSFs), and revised labeling for reregi strati on.
rodUCt Labeling All chlorhexidine diacetate end-use products must comply with EPA's
Changes current pesticide product labeling requirements and with the following.
quired Minimum (Baseline) PPE Requirements
The minimum (baseline) PPE for persons applying
chlorhexidine diacetate by mopping and hand wiping is:
"Applicators and other handlers must wear:
- Long sleeve shirt and long pants
- Socks plus shoes."
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The minimum (baseline) PPE for occupational uses of
chlorhexidine diacetate end-use products with the exception of the
wet-mist fogging is:
"Applicators and other handlers must wear:
- Long-sleeve shirt and long pants
- Chemical-resistant gloves
- Socks plus shoes."
For the wet-mist fogging, the following PPE is required:
"Applicators and other handlers exposed to the fog during wet-
mist fogging applications and until the fog has dissipated and
the enclosed area has been thoroughly ventilated must wear:
- Long-sleeve shirt and long pants
- Chemical-resistant gloves
- Socks plus shoes."
Regulatory The use of currently registered products containing
Conclusion chlorhexidine diacetate in accordance with approved labeling and as
specified in the RED will not pose unreasonable risks or adverse effects to
humans or the environment. Therefore, all uses of these products are
eligible for reregi strati on.
Chlorhexidine diacetate products will be reregistered once the
required product-specific data, revised Confidential Statements of Formula
and revised labeling are received and accepted by EPA.
For More EPA is requesting public comments on the Reregi strati on Eligibility
Information Decision (RED) document for [name] during a 60-day time period, as
announced in a Notice of Availability published in the Federal Register To
obtain a copy of the RED document or to submit written comments, please
contact the Pesticide Docket, Public Response and Program Resources
Branch, Field Operations Division (7506C), Office of Pesticide Programs
(OPP), US EPA, Washington, DC 20460, telephone
703-305-5805.
Electronic copies of the RED and this fact sheet can be downloaded
from the Pesticide Special Review and Reregi strati on Information System
at 703-308-7224. They also are available on the Internet on EPA's gopher
server, GOPHER.EPA.GOV, or using ftp on FTP.EPA.GOV, or using
WWW (World Wide Web) on WWW.EPA.GOV.
Printed copies of the RED and fact sheet can be obtained from EPA's
National Center for Environmental Publications and Information
(EPA/NCEPI), PO Box 42419, Cincinnati, OH 45242-0419, telephone
513-489-8190, fax 513-489-8695.
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Following the comment period, the [name] RED document also will
be available from the National Technical Information Service (NTIS), 5285
Port Royal Road, Springfield, VA 22161, telephone 703-487-4650.
For more information about EPA's pesticide reregistration program,
the Chlorhexidine diacetate RED, or reregistration of individual products
containing Chlorhexidine diacetate, please contact the Special Review and
Reregistration Division (7508W), OPP, US EPA, Washington, DC 20460,
telephone
703-308-8000.
For information about the health effects of pesticides, or for assistance
in recognizing and managing pesticide poisoning symptoms, please contact
the National Pesticides Telecommunications Network (NPTN). Call toll-
free 1-800-858-7378, between 9:30 am and 7:30 pm Eastern Standard
Time, Monday through Friday.
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
OFFICE OF
PREVENTION, PESTICIDES
AND TOXIC SUBSTANCES
OCT 29
CERTIFIED MAIL
Dear Registrant:
I am pleased to announce that the Environmental Protection Agency has completed its
reregistration eligibility review and decisions on the pesticide chemical case Chlorhexidine
diacetate which includes the active ingredient Chlorhexidine diacetate. The enclosed
Reregistration Eligibility Decision (RED) contains the Agency's evaluation of the data base of
these chemicals, its conclusions of the potential human health and environmental risks of the
current product uses, and its decisions and conditions under which these uses and products will
be eligible for reregistration. The RED includes the data and labeling requirements for
products for reregistration. It may also include requirements for additional data (generic) on
the active ingredients to confirm the risk assessments.
To assist you with a proper response, read the enclosed document entitled "Summary
of Instructions for Responding to the RED." This summary also refers to other enclosed
documents which include further instructions. You must follow all instructions and submit
complete and timely responses. The first set of required responses are due 90 days from
the receipt of this letter. The second set of required responses are due 8 months from the
receipt of this letter. Complete and timely responses will avoid the Agency taking the
enforcement action of suspension against your products.
Please note that this RED was finalized and signed prior to August 3, 1996. On that
date, the Food Quality Protection Act of 1996 ("FQPA") became effective, amending portions
of both the pesticide law (FIFRA) and the food and drug law (FFDCA). This RED does not
address any issues raised by FQPA, and any tolerance-related statements in the RED did not
take into account any changes in tolerance assessment procedures required under FQPA. To
the extent that this RED indicates that a change in any tolerance is necessary, that
determination will be reassessed by the Agency under the standards set forth in FQPA before
a proposed tolerance is issued. To the extent that the RED does not indicate that a change in
the tolerance is necessary, that tolerance, too, will be reassessed in the future pursuant to the
requirements of FQPA.
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If you have questions on the product specific data requirements or wish to meet with
the Agency, please contact the Special Review and Reregistration Division representative CP
Moran (703) 308-8590. Address any questions on required generic data to the Special Review
and Reregistration Division representative Bonnie Adler (703) 308-8523.
Sincerely yours,
Lois Rossi, Division Director
Special Review
and Reregistration Division
Enclosures
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SUMMARY OF INSTRUCTIONS FOR RESPONDING TO
THE REREGISTRATION ELIGIBILITY DECISION (RED)
1 DATA CALL-IN (PCI) OR "90-DAY RESPONSE"-If generic data are required for
reregistration, a DCI letter will be enclosed describing such data. If product specific data are
required, another DCI letter will be enclosed listing such requirements. If both generic and
product specific data are required, a combined Generic and Product Specific letter will be
enclosed describing such data. Complete the two response forms provided with each DCI
letter (or four forms for the combined) by following the instructions provided. You must
submit the response forms for each product and for each DCI within 90 days of the
receipt of this letter (RED issuance date); otherwise, your product may be suspended.
2. TIME EXTENSIONS AND DATA WAIVER REOUESTS-No time extension requests
will be granted for the 90-day response. Time extension requests may be submitted only with
respect to actual data submissions. Requests for data waivers must be submitted as part of the
90-day response. Requests for time extensions should be submitted in the 90-day response,
but certainly no later than the 8-month response date. All data waiver and time extension
requests must be accompanied by a full justification. All waivers and time extensions must be
granted by EPA in order to go into effect.
3 APPLICATION FOR REREGISTRATION OR "8-MONTH RESPONSE"-You
must submit the following items for each product within eight months of the date of this
letter (RED issuance date).
a. Application for Reregistration (EPA Form 8570-1). Use only an original
application form. Mark it "Application for Reregistration." Send your Application for
Reregistration (along with the other forms listed in b-e below) to the address listed in item 5
b Five copies of draft labeling which complies with the RED and current regulations
and requirements. Only make labeling changes which are required by the RED and current
regulations (40 CFR 156.10) and policies. Submit any other amendments (such as
formulation changes, or labeling changes not related to reregistration) separately. You may
delete uses which the RED says are ineligible for reregistration. For further labeling
guidance, refer to the labeling section of the EPA publication "General Information on
Applying for Registration in the U.S., Second Edition, August 1992" (available from the
National Technical Information Service, publication #PB92-221811; telephone number 703-
487-4650).
c Generic or Product Specific Data Submit all data in a format which complies
with PR Notice 86-5, and/or submit citations of data already submitted and give the EPA
identifier (MRID) numbers. Before citing these studies, you must make sure that they meet
the Agency's acceptance criteria (attached to the DCI).
d Two copies of the Confidential Statement of Formula (CSV) for each basic and
each alternate formulation. The labeling and CSF which you submit for each product must
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comply with PR Notice 91-2 by declaring the active ingredient as the nominal
concentration. You have two options for submitting a CSF: (1) accept the standard certified
limits (see 40 CFR § 1 58. 1 75) or (2) provide certified limits that are supported by the analysis
of five batches. If you choose the second option, you must submit or cite the data for the five
batches along with a certification statement as described in 40 CFR §158. 175(e) A copy of
the CSF is enclosed; follow the instructions on its back.
_, . e Certification With Respect to Data Compensation Reqnir^mpntc Complete
and sign EPA form 8570-3 1 for each product.
4 COMMENTS TN RESPONSE TO FEDERAT REGISTER NOTTrF-.ro ---- 1,
pertaining to the content of the RED may be submitted to the address shown in the Federal
Register Notice which announces the availability of this RED.
5 WHERE TO SEND PRODUCT SPECIFIC PCI RESPONSES (90-DAY1 ANn
APPLICATIONS FOR REREGISTRATTQN TS-MONTH RESPONSES! -
By U.S. Mail:
Document Processing Desk (RED-SRRD-PRB)
Office of Pesticide Programs (7504C)
EPA, 401 M St. S.W.
Washington, D.C. 20460-0001
By express:
Document Processing Desk (RED-SRRD-PRB)
Office of Pesticide Programs (7504C)
Room 266A, Crystal Mall 2
1921 Jefferson Davis Hwy.
Arlington, VA 22202
6. EPA'S REVIEWS-EPA will screen all submissions for completeness those which are
not complete will be returned with a request for corrections. EPA will try. to respond to data
waiver and time extension requests within 60 days. EPA will also try to respond to all 8-
month submissions with a final reregi strati on determination within 14 months after the RED
has been issued.
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REREGISTRATION ELIGIBILITY DECISION
Chlorhexidine diacetate
LISTC
CASE 3038
ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF PESTICIDE PROGRAMS
SPECIAL REVIEW AND REREGISTRATION DIVISION
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TABLE OF CONTENTS
CHLORHEXIDINE DIACETATE REREGISTRATION ELIGIBILITY DECISION
TEAM j
EXECUTIVE SUMMARY v
I. INTRODUCTION !
n. CASE OVERVIEW 2
A. Chemical Overview 2
B. Use Profile .... .2
C. Data Requirements 4
D. Regulatory History 4
III. SCIENCE ASSESSMENT 4
A. Physical Chemistry Assessment 4
B. Human Health Assessment 5
1. Toxicology Assessment 5
a. Acute Toxicity 5
b. Subchronic Dermal Toxicity 6
c. Chronic Toxicity/Carcinogenicity/Reproductive Toxicity 6
d. Developmental Toxicity 6
e. Mutagenicity 7
f. Toxicology Endpoints for Risk Assessment 7
g. Other Hazard Information 7
2. Exposure Assessment 8
a. Dietary Exposure g
b. Occupational Exposure 8
3. Risk Assessment 12
a. Dietary 12
b. Occupational 12
C. Environmental Assessment 13
1. Ecological Toxicity Data 14
a. Toxicity to Terrestrial Animals 14
b. Toxicity to Aquatic Animals 15
2. Environmental Fate 15
a. Environmental Fate Assessment 15
3. Exposure and Risk Characterization . 16
IV. RISK MANAGEMENT AND REREGISTRATION DECISION 16
A. Determination of Eligibility 16
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1. Eligibility Decision j7
B. Regulatory Position ,y
1. Human Exposure Risk Rationale 17
2. Personal Protective Equipment and Re-entry Requirements .18
V. ACTIONS REQUIRED OF REGISTRANTS 19
A. Manufacturing-Use Products 19
1. Additional Generic Data Requirements 19
B. End-Use Products 19
1. Additional Product-Specific Data Requirements ....... 19
2. Labeling Requirements for End-Use Products 20
C. Existing Stocks 24
VL APPENDICES
APPENDIX A. Table of Use Patterns Subject to Registration . 28
APPENDIX B. Table of the Generic Data Requirements and Studies Used to
Make the Reregistration Decision 34
APPENDIX C. Citations Considered to be Part of the Data Base Supporting
the Reregistration of Chloehexidine diacetate 38
APPENDIX D. Product Specific Data Call-in 45
Attachment 1. Chemical Status Sheets 59
Attachment 2. Product Specific Data Call-in Response Forms (Form
A inserts) Plus Instructions 60
Attachment 3. Product Specific Requirement Status and Registrant's
Response Forms (Form B inserts) and Instructions 64
Attachment 4. EPA Batching of End-Use Products for Meeting Data
Requirements for Reregistration 72
Attachment 5. List of All Registrants Sent This Data Call-in (insert)
Notice -4
Attachment 6. Cost Share, Data Compensation Forms, Confidential
Statement of Formula Form and Instructions 76
APPENDIX E. List of Available Related Documents '. 84
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CHLORHEXIDINE DIACETATE REREGISTRATION ELIGIBILITY DECISION
TEAM
Office of Pesticide Programs:
Biological and Economic Analysis Division
Frank Hernandez Economic Analysis Branch
Phyllis Johnson Biological Analysis Branch
Rafael Prieto Biological Analysis Branch
Environmental Fate and Effects Division
Karen Angulo Science Analysis and Coordination Staff
Laura Dye Ecological Effects Branch
Laura Parsons Environmental Fate and Groundwater Branch
Mary Powell Science Analysis and Coordination Staff
Health Effects Division
Thomas Campbell Occupational and Residential Exposure Branch
Kathleen Martin Risk Characterization and Analysis Branch
Irving Mauer Toxicology Branch I
Registration Division
Valdis Goncarovs Antimicrobial Program Branch
TinaLevine Registration Support Branch
Sami Malak Registration Support Branch
Special Review and Rereeistration Division
Bonnie Adler Accelerated Reregi strati on Branch
Kathy Davis Accelerated Reregistration Branch
Office of Research and Science Integration:
Vivian Turner Planning and Science Review Staff
Office of Enforcement and Compliance:
Rick Colbert Agricultural and Ecosystems Division
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11
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GLOSSARY OF TERMS AND ABBREVIATIONS
ADI
AE
a.i.
ARC
CAS
CI
CNS
CSF
DFR
DRES
DWEL
EEC
EP
EPA
FDA
FIFRA
FFDCA
FOB
GLC
GM
GRAS
HA
HOT
LC«
LD,
LEL
LOC
LOD
LOEL
MATC
MCLG
mg/L
MOE
MP
MPI
MRID
N/A
NOEC
Acceptable Daily Intake. A now defunct term for reference dose (RfD).
Acid Equivalent
Active Ingredient
Anticipated Residue Contribution
Chemical Abstracts Service
Cation
Central Nervous System
Confidential Statement of Formula
Dislodgeable Foliar Residue
Dietary Risk Evaluation System
Drinking Water Equivalent Level (DWEL) The DWEL represents a medium specific (i.e.
drinking water) lifetime exposure at which adverse, non carcinogenic health effects are not
anticipated to occur.
Estimated Environmental Concentration. The estimated pesticide concentration in an
environment, such as a terrestrial ecosystem.
End-Use Product
U.S. Environmental Protection Agency
Food and Drug Administration
Federal Insecticide, Fungicide, and Rodenticide Act
Federal Food, Drug, and Cosmetic Act
Functional Observation Battery
Gas Liquid Chromatography
Geometric Mean
Generally Recognized as Safe as Designated by FDA
Health Advisory (HA). The HA values are used as informal guidance to municipalities and
other organizations when emergency spills or contamination situations occur.
Highest Dose Tested
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/1, mg/kg or ppm.
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, inhalation). It
is expressed as a weight of substance per unit weight of animal, e.g., mg/kg.
Lethal Dose-low. Lowest Dose at which lethality occurs.
Lowest Effect Level
Level of Concern
Limit of Detection
Lowest Observed Effect Level
Maximum Acceptable Toxicant Concentration
Maximum Contaminant Level Goal (MCLG) The MCLG is used by the Agency to regulate
contaminants in drinking water under the Safe Drinking Water Act.
Micrograms Per Gram
Milligrams Per Liter
Margin of Exposure
Manufacturing-Use Product
Maximum Permissible Intake
Master Record Identification (number). EPA's system of recording and tracking studies
submitted.
Not Applicable
No effect concentration
ill
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GLOSSARY OF TERMS AND ABBREVIATIONS
NPDES
NOEL
NOAEL
OP
OPP
PADI
PAG
PAM
PHED
PHI
ppb
PPE
ppm
PRN
Q',
RBC
RED
REI
RfD
RS
SLN
TC
TD
TEP
TGAI
TLC
TMRC
ton
FAO/WHO
WP
WPS
National Pollutant Discharge Elimination System
No Observed Effect Level
No Observed Adverse Effect Level
Organophosphate
Office of Pesticide Programs
Provisional Acceptable Daily Intake
Pesticide Assessment Guideline
Pesticide Analytical Method
Pesticide Handler's Exposure Data
Preharvest Interval
Parts Per Billion
Personal Protective Equipment
Parts Per Million
Pesticide Registration Notice
The Carcinogenic Potential of a Compound, Quantified by the EPA's Cancer Risk Model
Red Blood Cell
Reregistration Eligibility Decision
Restricted Entry Interval
Reference Dose
Registration Standard
Special Local Need (Registrations Under Section 24 (c) of FIFRA)
Toxic Concentration. The concentration at which a substance produces a toxic effect.
Toxic Dose. The dose at which a substance produces a toxic effect.
Typical End-Use Product
Technical Grade Active Ingredient
Thin Layer Chromatography
Theoretical Maximum Residue Contribution
A unit of pressure needed to support a column of mercury 1 mm high under standard conditions
Food and Agriculture Organization/World Health Organization
Wettable Powder
Worker Protection Standard
IV
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EXECUTIVE SUMMARY
As required under the Federal Insecticide, Fungicide, and Rodenticide Act, as
amended in 1988, the U.S. Environmental Protection Agency has completed its reregi strati on
eligibility decision for the pesticide active ingredient chlorhexidine diacetate. This decision
includes a comprehensive reassessment of the required target data base and use patterns of
currently registered products. The Agency compared its risk assessment to current science
and regulatory policies. Where appropriate, it has imposed changes to the terms for continued
registration in order to reduce risks to human health and the environment.
The Agency has determined that the uses as described below will not cause
unreasonable risk to humans or the environment and all uses are eligible for reregi strati on
provided specified mitigation measures are adopted. These measures include the requirement
for product handlers to wear personal protective equipment (chemical resistant gloves, long-
sleeved shirts, long pants, shoes with socks and respirators). In addition, re-entry of workers
without personal protective equipment into areas treated by wet-mist fogging applications is
restricted until application is absorbed, set or dried and ventilation is complete.
Use Patterns
Chlorhexidine diacetate is used to control bacteria on agricultural premises and on
equipment, egg handling and packing equipment, meat processing plants, and for veterinary
hospital/clinic premises to control certain viruses.
Human Health Assessment
From its review of the toxicology data, the Agency concluded that chlorhexidine
diacetate is mildly to moderately toxic when administered by inhalation, oral and dermal
routes. However, in repeat primary eye irritation studies, the chemical is severely toxic. In a
subchfonic dermal rabbit toxicity study there was minimal dermal irritation observed at the
lowest dose tested, along with systemic effects: decreased enzyme activity with
microscopically observed degenerative changes in livers of low-dose females. This is
indicative of a chemical-induced hepatic effect. The 250 mg/kg/day dose was considered to
be a NOEL because of the minimal response observed at that dose. A battery of mutagenicity
studies were negative for mutagenic effects.
A developmental toxicology study with rats resulted in dose-related reduced body
weight gain, rales, and increased salivation. No observable malformations or significant
developmental toxicity were found at any dose level tested. The Agency concluded the
developmental toxicity NOEL is equal to or greater than the highest dose tested, 62.5
mg/kg/day, and the maternal toxicity NOEL is 15.63 mg/kg/day.
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There are no acute toxicological endpoints of concern for occupational uses of
chlorhexidine diacetate. For short- and intermediate-term exposures, the Agency's calculated
margins of exposure (MOE = NOEL/exposure) for chlorhexidine diacetate product handlers
(mixer/loaders/applicators) represent acceptable margins of exposure (MOEs * 100) for all
uses except the use in wet-mist foggers. Data were not available for the wet-mist fogger use,
therefore, MOEs were not calculated. To further reduce potential exposure the Agency is
imposing the use of personal protective equipment during any mixing/loading/application of
chlorhexidine diacetate products.
Environmental Assessment
Chlorhexidine diacetate is slightly toxic to practically nontoxic to avian species on an
acute and subacute oral dietary basis, moderately to highly toxic to fish, and very highly toxic
to aquatic invertebrates. Current uses of chlorhexidine diacetate, considered to be limited to
indoor, are expected to result in minimal exposure or risk to the environment. Therefore, no
environmental risk mitigation measures are being imposed at this time.
Product Reregi strati on
Before reregistering the products containing chlorhexidine diacetate, the Agency is
requiring that product specific data, revised Confidential Statements of Formula (CSF) and
revised labeling be submitted within eight months of the issuance of this document. These
data include product chemistry for each registration and acute toxicity testing. After
reviewing these data and any revised labels and finding them acceptable in accordance with
Section 3(c)(5) of FIFRA, the Agency will reregister a product. Those products that contain
other active ingredients will be eligible for reregi strati on only when the other active
ingredients are determined to be eligible for reregi strati on.
VI
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I. INTRODUCTION
In 1988, the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) was
amended to accelerate the reregi strati on of products with active ingredients registered prior to
November 1, 1984. The amended Act provides a schedule for the reregi strati on process to be
completed in nine years. There are five phases to the reregi strati on process. The first four
phases of the process focus on identification of data requirements to support the reregi strati on
of an active ingredient and the generation and submission of data to fulfill the requirements.
The fifth phase is a review by the U.S. Environmental Protection Agency (referred to as "the
Agency") of all data submitted to support reregi strati on.
FIFRA Section 4(g)(2)(A) states that in Phase 5 "the Administrator shall determine
whether pesticides containing such active ingredient are eligible for reregi strati on" before
calling in data on products and either reregistering products or taking "other appropriate
regulatory action." Thus, reregi strati on involves a thorough review of the scientific data base
underlying a pesticide's registration. The purpose of the Agency's review is to reassess the
potential hazards arising from the currently registered uses of the pesticide; to determine the
need for additional data on health and environmental effects; and to determine whether the
pesticide meets the "no unreasonable adverse effects" criterion of FIFRA.
This document presents the Agency's decision regarding the reregi strati on eligibility
of the registered uses of chlorhexidine diacetate. The document consists of six sections.
Section I is the introduction. Section II describes chlorhexidine diacetate, its uses, data
requirements and regulatory history. Section III discusses the human health and
environmental assessment based on the data available to the Agency. Section IV presents the
reregistration decision for chlorhexidine diacetate. Section V discusses the reregi strati on
requirements for chlorhexidine diacetate. Finally, Section VI is the Appendices which
support this Reregistration Eligibility Decision. Additional details concerning the Agency's
review of applicable data are available on request.
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H. CASE OVERVIEW
A. Chemical Overview
The following active ingredient is covered by this Reregistration Eligibility
Decision:
• Common Name: Chlorhexidine diacetate
• Chemical Name: 1,1'- hexamethylene bis [5-(p-chlorophenyl) biguanide]
diacetate
• CAS Registry Number: 56-95-1
• OPP Chemical Code: 045502
• Empirical Formula: C26H38C12N,0O4
• Trade and Other Names: Nolvasan, Bactigras
\
• Basic Manufacturer: Fort Dodge Laboratories
B. Use Profile
The following is information on the currently registered uses with an overview
of use sites and application methods. A detailed table of these uses of chlorhexidine
diacetate is in Appendix A.
For chlorhexidine diacetate:
Type of Pesticide: Limited disinfectant, virucide
Use Sites: Indoor Non-food: (with prescribed directions listed under Use
Practice Limitations)
Agricultural/Farm Premises
Egg Handling Equipment (commercial)
Egg Packing Plants (commercial)
Meat Processing Plant Equipment (food contact)
Meat Processing Premises (non-food contact)
-------
Poultry Processing Plant Equipment (food contact)
Poultry Processing Plant Premises (non-food contact)
Agricultural/Farm Equipment/Shoe Baths
Indoor Medical: (for veterinary uses only)
Medical Institutions/Premises
Target Pests:
Bacteria; Viruses: Canine distemper, Equine Influenza, Transmissible
Gastroenteritis, Hog Cholera, Parainfluenza 3, Bovine Rhinotracheitis, Bovine
Diarrhea, Infectious Bronchitis, Newcastle, Venezuelan Equine Encephalitis,
Equine Rhinopneumonitis, Feline Rhinotracheitis, Pseudorabies, Equine
Arteritis, Canine Coronavirus, Rabies.
Formulation Types Registered:
Form: End use product - 2% active ingredient soluble concentrate/liquid
Method and Rates of Application:
Types of Treatment: Animal feeding/watering equipment treatment, Surface
Treatment, Soak by saturation
Method and Rate (Concentrations)
Animal feeding/watering equipment treatment: 154 to 462 ppm a.i. by
weight
Surface Treatment: 154 to 462 ppm a.i. by weight
Soak: 157 ppm a.i. by weight
Use Practice Limitations:
Remove all animals and feed from premises, vehicles and other equipment prior
to treatment. Proper ventilation required. Do not house livestock or employ
equipment until treatment has been absorbed, set or dried. Thoroughly scrub
treated feed tracks, troughs, automatic feeders, fountains, and waterers with
soap or detergent, and rinse with potable water before reuse. All food products
and packaging material must be removed from the room or carefully covered
and protected. Remove any loose dirt, litter, etc., that might be lying on the
floor or attached to the equipment. Thoroughly clean all surfaces with soap or
detergent and rinse with water. Saturate all surfaces with the recommended
-------
disinfecting solution for a period of 10 minutes. Expose or soak all equipment
and/or utensils with the recommended disinfecting solution for a period of 10
minutes. After disinfection all equipment and/or utensils must be thoroughly
rinsed with potable water before operations are resumed. Nolvasan Solution
may be used in wet-mist fogging operations as an adjunct either preceding or
following regular cleaning and disinfecting procedures. Fog until the area is
moist using automatic foggers according to manufacturer's use directions.
Currently the regulation of teat dips and udder washes by the FDA is guided by
Compliance Policy Guide 7125.30 entitled, "Teat Dips and Udder Washes for
Dairy Cows and Goats."
C. Data Requirements
Data required by the Agency in the March 4, 1987 Antimicrobial Data Call-In
included mammalian toxicity and exposure data. The March 31, 1992 Phase IV Data
Call-In required studies on product chemistry, ecological effects, and environmental
fate. These data were required to support reregi strati on of the uses listed. Appendix B
includes all data requirements identified by the Agency for currently registered uses
needed to support reregi strati on.
D. Regulatory History
Products formulated with chlorhexidine diacetate as an active ingredient were
registered in the United States as early as 1955 for use as a farm premise
disinfectant/virucide. Later, products were registered for hospital settings but
eventually these uses were voluntarily cancelled. Currently, two end-use products
with 2% chlorhexidine diacetate are registered for use as hard surface-treatment
disinfectant/virucides.
III. SCIENCE ASSESSMENT
A. Physical Chemistry Assessment
The physical and chemical properties of the chlorhexidine diacetate technical
grade are summarized below:
Color: White
Physical State: Powdered Solid
Odor: Odorless
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Melting Point:
Bulk Density:
Solubilities:
pH:
Stability:
158.7°C
1.2 gm/cm3
Solvent Solubility
Water Solubilizes
Ethanol 6.7 gm/100 ml
Glycerol.'... slightly soluble
Propane slightly soluble
6.8 (in 1% solution)
Stable under ambient warehouse conditions to
moisture and simulated sunlight.
B. Human Health Assessment
1. Toxicology Assessment
The toxicology data base for chlorhexidine diacetate (1,1'-
hexamethylene bis[5-(p-chlorophenyl)biguanide]diacetate) is adequate and will
support reregi strati on eligibility.
a. Acute Toxicity
Chlorhexidine diacetate has been evaluated for acutely toxic
effects. Table 1 summarizes the results of the submitted studies.
•>,
Table 1. Acute Toxicity
Test (Guideline)
2000 mg/kg
LC50 (males) = 0.30 mg/L
LC50 (females) = 0.43 mg/L
PII = 66.4
PIS = 0.0
Not a sensitizer
Toxi<% SO
Category
III
III
II
I
IV
N/A
here for informational purposes
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The technical grade active ingredient (97.7 percent to 98.3
percent ai) is mildly (toxicity category III and IV) to moderately
(toxicity category II) acutely toxic when administered by dermal, oral
and inhalation routes. In a repeat primary eye irritation study,
chlorhexidine diacetate was severely toxic (toxicity category I).
b. Subchronic Dermal Toxicity
Subchronic toxicity data were submitted from a 13-week dermal
toxicity study on New Zealand White rabbits that were treated topically
at chlorhexidine diacetate doses of 0, 250, 500, or 1000 mg/kg/day
(MRID 40952201). These data satisfy the requirement for this type of
assay. Minimal dermal irritation (erythema, edema, desquamation
and/or fissuring) was evident at the lowest dose tested (250 mg/kg/day).
In addition, the finding of decreased enzyme activity, coupled with
microscopically-observed degenerative changes in the liver are
indicative of a hepatic effect in females at this dose level; (systemic)
liver effects were noted at the 500 mg/kg/day level. However, for
occupational exposure risk assessment purposes, the 250 mg dose is
considered to be a NOEL because of the minimal response observed at
that dose.
c. Chronic Toxicity/Carcinogenicity/Reproductive Toxicity
Oral chronic toxicity studies are not required for this use pattern.
d. Developmental Toxicity
Acceptable developmental toxicity data were provided in a study
using Sprague-Dawley rats that were dosed by gavage at 0, 15.63,
31.25, or 62.5 mg/kg/day; gestation dosing was done at days six through
15 (MRID 42102101). From this study a maternal toxicity NOEL for
orally-administered chlorhexidine diacetate was established at 15.63
mg/kg/day. Higher doses resulted in dose-related reduced body weight
gain, rales, and increased salivation (LOEL of 31.25 mg/kg/day, and a
HDT of 62.5 mg/kg/day). No observable malformations or
developmental toxicity were found at any dose level tested. The
developmental toxicity NOEL is equal to or greater than the highest
dose, 62.5 mg/kg/day.
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e. Mutagenicity
Acceptable data were submitted for a battery of mutagenicity
studies that assayed for the potential of chlorhexidine diacetate to
induce changes in several genetic endpoints (MRIDs 40231003,
40231004, and 40231005). The technical formulation tested negative
for gene mutation up to cytotoxic levels (6 fig/ml in non-activated
assays and 15-16 ug/ml in activated assays) with mammalian mouse
lymphoma cells in culture. Negative results were also obtained in in
vitro cytogenetic assays with Chinese hamster ovary cells (negative for
chromosomal breakage, with and without activation at test levels up to
10 ug/ml, that reduced cell growth 30 percent of control). Similarly,
there was no DNA damage/repair in a study using primary rat
hepatocyte cultures (negative for increased net nuclear counts at 18
hours with exposure levels up to 2.42 ug/ml).
A singular test for gene mutation with bacteria
(Salmonella/Ames Assay) reported negative results, but this study was
considered unacceptable due to major procedural deficiencies. The
studies discussed above are more appropriate for an evaluation of
genotoxic potential of an antimicrobial agent. Therefore, a new
Salmonella test is not required.
f. Toxicology Endpoints for Risk Assessment
Toxicology Endpoints
The endpoints for chlorhexidine diacetate were established by
the HED Less-Than-Lifetime Exposure committee on May 16, 1995.
Short-term occupational or residential exposure (one to seven days) had
a NOEL of 250 mg/kg based on systemic (liver) effects at 500 mg/kg
from a 13-week dermal toxicity study (MRBD 40952201). Intermediate
term occupational/residential exposure (one week to several months)
and chronic exposure indicated the same endpoints as the short-term
exposures accompanied by severe skin effects (MRID 40952201). An
endpoint for acute dietary exposures is not required for this active
ingredient.
g. Other Hazard Information
A review of Agency incident data shows that there are two
recorded anecdotal reports of human reactions to chlorhexidine
diacetate products (OPP-Incident Data System, 04/10/95). However,
-------
these reactions do not alter the conclusions the Agency has drawn from
the toxicology database because both incidents were associated with
product misuse.
2. Exposure Assessment
a. Dietary Exposure
Chlorhexidine diacetate is registered for use in federally
inspected meat, poultry, egg, and rabbit processing plants, as a
disinfectant on processing surfaces. The labeling for these products
requires that food products and packaging materials are removed or
carefully covered prior to application and that a potable water rinse is
employed after treatment. The U.S. Department of Agriculture and the
EPA have determined that disinfectants, when applied to federally
inspected meat, poultry, egg, and rabbit processing plants as described
above, do not present dietary exposure risks (USDA, FSIS publication
#1419, "List of Proprietary Substances and Nonfood Compounds").
b. Occupational Exposure
The Agency has determined that an exposure assessment is
required for chlorhexidine diacetate based on the toxicity endpoint from
the subchronic dermal study (MRID 40952201) described above. The
registrant is a participant in the Chemical Manufacturer's Association
(CMA) Antimicrobial Exposure Assessment study, therefore, data from
that study were used in the exposure assessment (MRIDs 41412201,
41742601, and 42587501). No dermal absorption data on chlorhexidine
diacetate exists, therefore, the Agency assumes 100% absorption.
Application methods include open-pouring, wet-mist fogging,
surface wiping, mopping, low- and high-pressure spray applications.
EPA assumes the frequency of repeated product application can be 50 to
250 times per year, depending upon the type of application.
Handler Exposure
The Agency has determined that mixers, loaders, applicators and
other handlers may be potentially exposed to chlorhexidine diacetate
during normal use and application of products. Specifically, EPA has
focused on exposures to loaders and applicators using chlorhexidine
diacetate to disinfect veterinary and/or farm premises or animal-product
processing facilities.
-------
Based on the use pattern, several exposure scenarios are
plausible as defined by the use-site. The potential exposure scenarios
include (1) open-pour loading of liquid formulations, (2) applying the
disinfectant by hand by wiping surfaces, (3) applying the disinfectant by
hand by dipping tools/implements into dilute disinfectant solution, (4)
applying the disinfectant by mopping surfaces, (5) applying the
disinfectant with hand-held high-pressure spray equipment, (6) applying
the disinfectant with hand-held low-pressure spray equipment, and (7)
applying the disinfectant with a wet-mist fogger (automatic fogger).
Table 2 provides the exposure estimates for the above scenarios,
except for applications by hand by dipping tools/implements into the
dilute disinfectant solution and applications with a wet-mist fogger.
EPA believes that exposures to applicators applying the disinfectant by
wiping is a reasonable surrogate for applying by dipping
tools/implements into the disinfectant. The exposure estimates range
from 14.7 //g/kg/day for application by mop (no gloves) to 572
//g/kg/day for application with a wipe (no gloves) based on amortized
average daily doses. The exposure data were derived from the CMA
study where workers wore (except where noted) long-sleeved shirts,
long pants, and chemical resistant gloves. Please note that the CMA
study does not provide data for the wet-mist fogger; therefore, no
exposure assessment was conducted for this scenario.
The unit exposure (UE) is a combination of both dermal and
inhalation exposure values. The dermal exposure component of the UE
was derived from the sum of dermal deposition measurements that were
taken at multiple body locations. Dermal deposition measurements that
were less than the level of detection (i.e. non-detects) were included in
the calculation at one-half of the limit of detection Attempts to
measure the inhalation exposure resulted in non-detectable values.
Therefore, the inhalation exposure component was added at one-half of
the limit of detection to the dermal exposure component; the inhalation
exposure component is considered to be minimal in comparison to the
dermal exposure component.
EPA estimated the volume of disinfectant solution used per day
for the low-pressure and high-pressure hand-held spray equipment as 40
and 100 gallons per day, respectively. These estimates are higher than
the volume per day estimated in the CMA studies because of the
relatively larger size of the treated areas (meat- and poultry-processing
premises and egg-laying facilities) for some of the use scenarios.
-------
Post-Application Exposure
EPA believes there are potential exposures to persons reentering
areas that have been treated with chlorhexidine diacetate, especially
following wet-mist fogging applications and other applications in
enclosed areas. Exposures from wet-mist fogging are not quantified
because unlike the other application scenarios where some handler data
are available (i.e., the CMA data), neither handler nor post-application
data are available for this scenario.
Due to the toxicological characteristics of chlorhexidine
diacetate, the Agency has determined that a post-application exposure
assessment is appropriate. However, there are no data available to
directly assess any post-application exposure scenario. Therefore, only
a qualitative assessment can be done. EPA believes it is reasonable to
assume that post-application exposures of workers to chlorhexidine
diacetate are much lower than exposure to occupational handlers. This
assumption is based on the belief that handlers
(mixers/loaders/applicators) will have more dermal contact with the
pesticide than a person who has incidental contact with a treated
surface.
10
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Table 2. Exposure Estimates for Chlorhexidine Diacetate Use Scenarios
SCENARIO
Pour Liquid
High Pressure Spray
Low Pressure Spray
(ungloved)
Wipe (ungloved)
Mop (ungloved)
Wet-Mist Fogger
USE
Disinfectant
Disinfectant
Disinfectant
Disinfectant
Disinfectant
Disinfectant
AMOUNT OF PESTICIDE ;
USED PER BAY i
USE
RATE
(c*/g*l)
32
3
3
3
3
1
VOLUME USED/DAY
{gallons)
100
100
40
5
5
no data
8»« i
used/day i
4.15
0.4
0.16
0.02
0.02
no data
WORKER EXPOSURE
m./ •
(ug/lb*t}
35,490
299,680
190,560
2,922,645
75,280
no data
BW
fr&
70
70
70
70
70
70
££ ''•
50
50
50
250
250
no data
ADE :
l&gikgAky)
2104
1710
436
835
21.5
no data
ABiD
(HgrtcgAJayJ
288
235
59.6
572
14.7
no data
EXPLANATORY NOTES:
USE RATE = The amount of 2% ai Nolvasan solution diluted into a gallon of water The indicated rate is the maximum label rate.
VOLUME USED/DAY = The amount of solution used per day. This was obtained from the CMA study.
UE = Unit Exposure, which was derived from the CMA Study.
BW = Body Weight, which is assumed to be 70 kg.
EF = Exposure Frequency, which is the number of times the product is applied per year. This information was obtained from the CMA study.
ADE = Actual Daily Exposure.
ADD = amortized Average Daily Dose.
FORMULAS:
Ibai
used/day
= Use Rate
(oz/gal)
x %a x Vol. used/day x
i (gal)
gal/ 128 oz x 8.3 Ib/gal
ADE
(Hg/kg/day)
(Unit Exposure x Ib ai used/day) +
(Hg/lb ai)
ADD
(Hg/kg/day)
= ADE x EF(days)/365
(Hg/kg/day) days
BW
(kg)
11
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3. Risk Assessment
a. Dietary
A risk assessment from dietary exposures'to chlorhexidine
diacetate is not required, based on the current use pattern. The U.S.
Department of Agriculture and the EPA have determined that
disinfectants, when applied to federally inspected meat, poultry, egg,
and rabbit processing plants as described previously, do not present
dietary exposure risks.
b. Occupational
Based on available toxicity data and use patterns for
chlorhexidine diacetate, the Agency has determined that risk
characterizations for mixer/loader/applicators (occupational) and post-
application exposures are appropriate. Because of the selected
toxicology endpoint for chlorhexidine diacetate, the Agency is
characterizing the risks by margins of exposure (MOE), that is, the ratio
of the toxicological endpoint NOEL to the estimate of exposure. The
Agency is using the calculated units of exposure from Table 2: actual
daily exposure (ADE) for short and intermediate term exposures and the
amortized average daily exposure (ADD) for chronic exposures.
Formulas for these risk calculations are as follows:
Formulas for MOE Calculations
Margin-of-Exposure (MOE)
(short and intermediate}
NOEL
(ug/kg/day)
+ ADE
(ug/kg/day)
Margin-of-Exposure (MOE)
(chronic)
NOEL
(Ug/kg/day)
- ADD
(ug/kg/day)
Mixer/Loader/Applicator (Handler) Risk
Adequate data are available to characterize the occupational risk
for most handler exposure scenarios. A summary of MOE calculations
for each of the five use scenarios is provided in Table 3. These MOEs
range from 119 for the Pour Liquid Scenario to 17,007 for the Mop
12
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Scenario (ungloved). These values are greater than 100 which is the
Agency's regulatory level of concern threshold for noncarcinogenic
endpoints. Therefore, exposures to handlers in these scenarios are not
of concern to the Agency.
Table 3. Margins of Exposures for Handler Exposure
SCENARfO
Pour Liquid
High Pressure Spray
Low Pressure Spray (ungloved)
Wipe (ungloved)
Mop (ungloved)
MOB
(short and intermediate
exposure)
119
146
573
299
11,628
MQE
. {chronic
exposure)
Not Applicable"
Not Applicable*
Not Applicable*
437
17,007
NOEL = 250 mg/kg/day
* Sued on expoiure frequency of 50 Ome» a year. EPA doa not consider this icenano to be chronic
The CMA study does not provide data for the wet-mist fogger
method of application. While EPA cannot estimate levels of exposure
or MOEs for this scenario, EPA is concerned about potential inhalation
and ocular exposures to applicators during fogging and other workers
who may enter the treated area before the fog has dissipated.
Post-Application Risk
A
There are no data available to directly assess potential exposures
to chlorhexidine diacetate by post-application workers. However, EPA
assumes that exposures to occupational handlers are much higher than
post-application exposures to occupational workers, provided entry into
treated areas is restricted immediately following applications. Because
all the MOEs for occupational handlers are greater than 100, EPA
believes that occupational exposures to post-application workers would
not be of concern, provided that the product is used in accordance with
label instructions as specified in this document.
C. Environmental Assessment
For chlorhexidine diacetate, like other pesticides whose uses are limited to
indoor sites, the Agency requires only a limited set of ecotoxicology and
environmental fate studies. Minimal to no environmental exposure is expected from
the indoor use patterns. For this reason, the Agency does not routinely conduct full
13
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environmental assessments on pesticides limited to indoor uses. Therefore, this has
not been done for chlorhexidine diacetate. However, the Agency recognizes that a
limited set of studies are necessary to have in order to characterize such a pesticide's
hazard potential in the case of unanticipated environmental exposures caused by
transportation accidents, spills, or improper disposal or use. These studies for
chlorhexidine diacetate have been submitted, are acceptable and fulfill the guideline
requirements. The conclusions are reported below.
1. Ecological Toxicity Data
The ecotoxicological data base is adequate to characterize the toxicity of
chlorhexidine diacetate to nontarget terrestrial and aquatic organisms when it is
used as an indoor nonfood antimicrobial.
a. Toxicity to Terrestrial Animals
(1) Birds, Acute and Subacute
To establish the toxicity of chlorhexidine diacetate to
birds, the following tests were conducted using the technical
grade material: one avian single-dose oral (LD50) study on the
bobwhite quail; and two subacute dietary studies (LC^) on the
mallard duck and the bobwhite quail. Tables 4 and 5 summarize
these three studies.
Table 4. Avian Acute Oral Toxicity Findings (LD5,620
>5,620
MR1D No.
Author/Year
42197502, Long, Hoxter & el., 1991
42 197503, Long, Hoxter& el., 1991
Toxicity Category
practically nontoxic
practically nontoxic
These results indicate that chlorhexidine diacetate is
slightly toxic to practically nontoxic to avian species based on
acute and subacute dietary data (MRIDs 42197501, 42197502
and 42197503).
14
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b. Toxicity to Aquatic Animals
(1) Freshwater Fish
The 96-hour acute toxicity studies were conducted on two
species of freshwater fish - a coldwater species (rainbow trout)
and a warmwater species (bluegill sunfish). The results of these
studies indicate that chlorhexidine diacetate is moderately to
highly toxic to freshwater fish (MRIDs 42197504 and
42197505). Table 6 summarizes these studies.
Table 6. Freshwater Fish Acute Toxicity Findings
Species
Rainbow trout
Bluegill sunfish
%AJ.
100.78
100.78
LCjg ppm
1.9
0.6
MRID No., Author/Year
42197504
Murphy & Smith, 1991
42197505
Murphy & Smith, 1991
Toxicity
Category
moderately
toxic
highly toxic
(2) Freshwater Invertebrates
The freshwater aquatic invertebrate toxicity test using
Daphnia magna characterizes chlorhexidine diacetate as very
highly toxic to aquatic invertebrates (MRID 42197506). Table 7
shows these results.
Table 7. Freshwater Invertebrate Toxicity Findings
Species
Daphnia magna
%A.I.
100.78
EC,0(mg/l)
0.06
MRID No.
Author/Year
42197506
Murphy & Smith, 1991
Toxicity Category
very highly toxic
2.
Environmental Fate
a.
Environmental Fate Assessment
For chlorhexidine diacetate the Agency did not conduct an
environmental fate assessment because it is unlikely for the environment
to be exposed to the pesticide when it is used as labeled.
A conjectural environmental fate assessment could be that
chlorhexidine diacetate would probably decompose by microbial
metabolism and that the parent compound is probably mobile in soil
systems. The rationale for this assessment is that chlorhexidine is a very
15
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large molecule (C22H30Cl2Ni0; molecular weight 505.5 g/mole) with
several carbon-carbon and carbon-nitrogen bonds that are probably
vulnerable to microbial decomposition. Chlorhexidine diacetate is very
water soluble at 19 g/L water at 20 °C, which can indicate mobility in a
soil system. Also, according to the Merck Index, aqueous solutions of
chlorhexidine diacetate decompose at temperatures higher than 70 °C,
so the inference can be made that chlorhexidine diacetate probably does
not hydrolyze at lower temperatures.
3. Exposure and Risk Characterization
As explained above, the Agency does not conduct an assessment of the
risk to nontarget organisms for pesticides having indoor uses without effluents,
as is the case for chlorhexidine diacetate. From the available data, the Agency
concludes that chlorhexidine diacetate is slightly toxic to practically nontoxic to
avian species on an acute oral and subacute dietary basis, moderately to highly
toxic to fish, and very highly toxic to aquatic invertebrates. However, the
indoor uses of chlorhexidine diacetate are expected to result in minimal
exposure to the environment.
IV. RISK MANAGEMENT AND REREGISTRATION DECISION
A. Determination of Eligibility
Section 4(g)(2)(A) of FIFRA calls for the Agency to determine, after
submission of relevant data concerning an active ingredient, whether products
containing the active ingredients are eligible for reregi strati on. The Agency has
previously identified and required the submission of the generic (i.e. active ingredient
specific) data required to support reregi strati on of products containing chlorhexidine
diacetate active ingredients. The Agency has completed its review of these generic
data, and has determined that the data are sufficient to support reregistration of all
products containing chlorhexidine diacetate. Appendix B identifies the generic data
requirements that the Agency reviewed as part of its determination of reregistration
eligibility of chlorhexidine diacetate, and lists the submitted studies that the Agency
found acceptable.
The data identified in Appendix B are sufficient to allow the Agency to assess
the registered uses of chlorhexidine diacetate and to determine that chlorhexidine
diacetate can be used, as specified in this document, without resulting in unreasonable
adverse effects to humans and the environment. The Agency therefore finds that all
products containing chlorhexidine diacetate as the active ingredient and with the
modifications as stipulated in this document are eligible for reregistration. The
reregistration of particular products is addressed in Section V of this document.
16
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The Agency made its reregi strati on eligibility determination based upon the
target data base required for reregistration, the current guidelines for conducting
acceptable studies to generate such data, published scientific literature, etc. and the
data identified in Appendix B. Although the Agency has found that all uses of
chlorhexidine diacetate are eligible for reregistration, it should be understood that the
Agency may take appropriate regulatory action, and/or require the submission of
additional data to support the registration of products containing chlorhexidine
diacetate, if new information comes to the Agency's attention or if the data
requirements for registration (or the guidelines for generating such data) change.
1. Eligibility Decision
Based on the reviews of the generic data for the active ingredient
chlorhexidine diacetate, the Agency has sufficient information on the health
effects of chlorhexidine diacetate and on its potential for causing adverse
effects in fish and wildlife and the environment. The Agency has determined
that chlorhexidine diacetate products, labeled and used as specified in this
Reregistration Eligibility Decision, will not pose unreasonable risks or adverse
effects to humans or the environment. Therefore, the Agency concludes that
products containing chlorhexidine diacetate for all uses are eligible for
reregistration.
2. Eligible and Ineligible Uses
The Agency has determined that all currently registered uses of
chlorhexidine diacetate are eligible for reregistration.
B. Regulatory Position
The following is a summary of the regulatory positions and rationales for
chlorhexidine diacetate. Where labeling revisions are imposed, specific language is
set forth in Section V of this document.
1. Human Exposure Risk Rationale
The Agency has determined that mixer/loader/applicator exposures to
chlorhexidine diacetate are not of concern based on margins of exposure that
range from 119 to over 17,000. These margins of exposure are based on all use
scenarios except the wet-mist fogger. EPA is concerned about potential
exposures, particularly inhalation and ocular exposures, to applicators and
other workers exposed to chlorhexidine diacetate fogs. To reduce exposures
and risk, the Agency is imposing PPE requirements.
17
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The Agency also believes that post-application occupational exposures
are not of concern provided entry into treated areas is restricted immediately
following applications and ventilation is complete. Post-application exposure
is likely to be lower than exposure to pesticide handlers.
2. Personal Protective Equipment and Re-entry Requirements
For each end-use product, PPE requirements for pesticide handlers are
set during reregistration in one of two ways:
1 If EPA determines that no regulatory action must be taken as the result of the
acute effects or other adverse effects of an active ingredient, the PPE for
pesticide handlers will be based on the acute toxicity of the end-use product.
For occupational-use products, PPE must be established using the process
described in PR Notice 93-7 or more recent EPA guidelines.
2. If EPA determines that regulatory action on an active ingredient must be
taken as the result of very high acute toxicity or to certain other adverse effects,
such as allergic effects or delayed effects (cancer, developmental toxicity,
reproductive effects, etc.):
• In the RED for that active ingredient, EPA may establish minimum or
"baseline" handler PPE requirements that pertain to all or most end-use
products containing that active ingredient.
• These minimum PPE requirements must be compared with the PPE that
would be designated on the basis of the acute toxicity of the end-use
product.
• The more stringent choice for each type of PPE (i.e., body wear, hand
protection, footwear, eyewear, etc.) must be placed on the label of the
end-use product.
Personal protective equipment requirements usually are set by
specifying one or more pre-established PPE units - sets of items that are
almost always required together. For example, if chemical-resistant gloves are
required to mitigate risk, then long-sleeve shirts, long pants, socks, and shoes
are also included in the required minimum attire. If the requirement is for two
layers of body protection (coveralls over a long- or short-sleeve shirt and long
or short pants), the minimum must also include (for all handlers) chemical-
resistant footwear and chemical-resistant headgear for overhead exposures and
(for mixers, loaders, and persons cleaning equipment) chemical-resistant
aprons.
18
-------
Personal protective equipment requirements, described in Section V of
this document, are indicative of the dermal protection used in the CMA study,
in which most study subjects wore long-sleeve shirts and long pants, chemical
resistant gloves, shoes and socks. Estimated units of exposure and risk (MOEs)
for chlorhexidine diacetate were based on this fact. In addition, because of
EPA's presumption that workers entering areas during or after fogging
applications before adequate ventilation could receive exposures to
chlorhexidine diacetate, inhalation and ocular protection is also required for
persons exposed to the wet-mist fog. Label statements for PPE are provided
for occupational uses.
V. ACTIONS REQUIRED OF REGISTRANTS
This section specifies the data requirements and responses necessary for the
reregi strati on of both manufacturing-use and end-use products.
A. Manufacturing-Use Products
1. Additional Generic Data Requirements
The generic data base supporting the reregi strati on of chlorhexidine
diacetate for the above eligible uses has been reviewed and determined to be
substantially complete.
B. End-Use Products
1. Additional Product-Specific Data Requirements
Section 4(g)(2)(B) of FIFRA calls for the Agency to obtain any needed
product-specific data regarding the pesticide after a determination of eligibility
has been made. The product specific data requirements are listed in Appendix
G, the Product Specific Data Call-In Notice.
Registrants must review previous data submissions to ensure that they
meet current EPA acceptance criteria (Appendix F; Attachment E) and if not,
commit to conduct new studies. If a registrant believes that previously
submitted data meet current testing standards, then study MRID numbers
should be cited according to the instructions in the Requirement Status and
Registrants Response Form provided for each product.
19
-------
2. Labeling Requirements for End-Use Products
Persona] Protective Equipment Requirements for Pesticide
Handlers
For sole-active-ingredient end-use products that contain chlorhexidine
diacetate, the product labeling must be revised to adopt the handler personal
protective equipment (PPE) requirements set forth in this section. Any
conflicting PPE requirements on the current labeling must be removed.
For multiple-active-ingredient end-use products that contain
chlorhexidine diacetate, the handler PPE requirements set forth in this section
must be compared to the requirements on the current labeling and the more
protective must be retained. For guidance on which requirements are
considered more protective, see PR Notice 93-7.
Products Intended Primarily for Occupational Use ~
Application
Minimum (Baseline^ PPE Requirements
The minimum (baseline) PPE for persons applying
chlorhexidine diacetate with mopping and hand wiping is:
"Applicators and other handlers must wear:
Long sleeve shirt and long pants
Socks plus shoes."
The minimum (baseline) PPE for occupational uses of
chlorhexidine diacetate end-use products with the exception of
the wet-mist fogging is:
"Applicators and other handlers must wear:
Long-sleeve shirt and long pants
Chemical-resistant gloves*
Socks plus shoes."
* For the glove statement, use the statement established for
chlorhexidine diacetate through the instructions in Supplement 3
of PR Notice 93-7.
20
-------
For the wet-mist fogging, the following PPE is required:
"Applicators and other handlers exposed to the fog during
wet-mist fogging applications and until the fog has
dissipated and the enclosed area has been thoroughly
ventilated, they must wear:
Long-sleeve shirt and long pants
Chemical-resistant gloves*
Socks plus shoes
A full face respirator with a canister approved for
pesticides (MSHA/NIOSH approval number
prefix TC-14G)."
* For the glove statement, use the statement established for
chlorhexidine diacetate through the instructions in Supplement 3
of PR Notice 93-7.
Determining PPE Requirements for End-Use Product Labels
The PPE that would be established on the basis of the acute
toxicity category of the end-use product must be compared to the active-
ingredient-based minimum (baseline) PPE specified above. The more
protective PPE must be placed on the product labeling. For guidance on
which PPE is considered more protective, its placement, format, and
wording refer to PR Notice 93-7.
Entry Restrictions
For sole-active-ingredient end-use products that contain
chlorhexidine diacetate, the product labeling must be revised to adopt
the entry restrictions set forth below. Any conflicting entry restrictions
on the current labeling must be removed.
For multiple-active-ingredient end-use products that contain
chlorhexidine diacetate the entry restrictions set forth in this section
must be compared to the entry restrictions on the current labeling and
the more protective must be retained. A specific time period in hours or
days is considered more protective than"sprays have dried" or "dusts
have settled."
21
-------
Products Intended Primarily for Occupational Use - Post-
Application
Entry Restrictions
The Agency is establishing the following entry restrictions for all
occupational uses of chlorhexidine diacetate end-use products:
"Thoroughly ventilate buildings, vehicles, and closed spaces
following application. Do not enter, allow other persons to
enter, house livestock, or use equipment in the treated area until
ventilation is complete and the liquid chlorhexidine diacetate has
been absorbed, set, or dried."
For wet-mist fogging applications add:
"For entry into fogged areas before ventilation is complete and
the fog has completely dissipated, absorbed, set or dried, all
persons must wear:
Long sleeved shirt
Long pants
Chemical-resistant gloves*
Socks plus shoes
A full-face respirator with a canister approved for
pesticides (MSHA/NIOSH approval number
prefix TC-14G)."
* For the glove statement, use the statement established for
chlorhexidine diacetate through the instructions in Supplement 3
of PR Notice 93-7.
Other Labelling Requirements for Products Intended Primarily
for Occupational Use
The Agency is requiring the following labeling statements to be
located on all end-use products containing chlorhexidine diacetate that
are intended primarily for occupational use:
Application Restrictions (This statement is required on all end-use
product labeling where spray or fog applications are permitted.)
22
-------
"Do not apply this product in a way that will
contact workers or other persons, either directly or
through drift. Only protected handlers may be in
the area during application."
User Safety Requirements
The registrant must place the following statement on the end-use
product label only if coveralls are required for pesticide handlers:
"Discard clothing or other absorbent materials that have been
drenched or heavily contaminated with this product's
concentrate. Do not reuse them."
The registrant must place the following statement on all end-use product
labels:
"Follow manufacturer's instructions for cleaning/
maintaining personal protective equipment. If there are
no such instructions for washables, use detergent and hot
water. Keep and wash personal protective equipment
separately from other laundry."
User Safety Recommendations
"Users should wash hands before eating, drinking,
chewing gum, using tobacco, or using the toilet."
"Users should remove clothing immediately if
pesticide gets on or inside it. Then wash both skin
and clothing thoroughly and put on clean clothes."
"Users should remove personal protective
equipment immediately after handling this
product. Wash the outside of gloves before
removing. As soon as possible, wash skin and
clothing thoroughly and change into clean
clothes."
Other Labeling Requirements
The label directions as specified in the Agency's labeling
document entitled, "Label Requirements for Farm Premise
23
-------
Disinfectants," number DIS/TSS-18, dated January 17, 1980, are
required for farm premise disinfectants to permit their classification as
non-food use products.
The following label directions are required for meat, poultry,
rabbit and egg establishment disinfectants to permit their classification
as non-food use products:
"All food products and packaging material must be
removed from the room or carefully covered and
protected.
Remove any loose dirt, litter, etc., that might be lying on
floor or attached to the equipment.
Thoroughly clean all surfaces with soap or detergent and
rinse with water.
Saturate all surfaces with the recommended disinfecting
solution for a period of 10 minutes.
Expose or soak all equipment and/or utensils with the
recommended disinfecting solution for a period of 10
minutes.
After disinfection all equipment and/or utensils must be
thoroughly rinsed with potable water before operations
are resumed."
The registrant must specify the application method equipment
and timing on all labeling.
C. Existing Stocks
Registrants may generally distribute and sell products bearing old
labels/labeling for 26 months from the date of the issuance of this Reregi strati on
Eligibility Decision (RED). Persons other than the registrant may generally distribute
or sell such products for 50 months from the date of the issuance of this RED.
However, existing stocks time frames will be established case-by-case, depending on
the number of products involved, the number of label changes, and other factors. Refer
to "Existing Stocks of Pesticide Products; Statement of Policy;" Federal Register
Volume 56, No. 123, June 26, 1991.
24
-------
The Agency has determined that registrants may distribute and sell
chlorhexidine diacetate products bearing old labels/labeling for 26 months from the
date of issuance of this RED. Persons other than the registrant may distribute or sell
such products for 50 months from the date of the issuance of this RED. Registrants
and persons other than registrants remain obligated to meet pre-existing Agency
imposed label changes and existing stocks requirements applicable to products they
sell or distribute.
25
-------
26
-------
VI. APPENDICES
-------
Report Run Bate: 10/05/95 - Time 11:17
Case 3038[Chlorhexidine derivs.]
LUIS 2.2 Page: 1
APPENDIX A REPORT
Chemical 045502[Chlorhexidine diacetate)
Timing, Application Equipment - Rate (AI un Rate IAI Tex a M R t i S Restr. Geographi.
Surface Type (Antimicrobial only) 4 Effica- less noted unless noted Max! /crop /year othe™ise)/A| (d^T Tt^ A11°Wed
cy Influencing Factor (Antimicrobial only) otherwise) otherwise) Dose cycle /crop /year * (day^) ]
cycle
WON - FOOD /NON- FEED
SSRICULTUR&L/WSR8 EWr?WEB3y$80B BftlHS 0Sa <3eo<3p< IJJDOOR SCJJ~POOD
Immersion, Not on label. Not on label, SC/L W 154 W 154 * NS NS Ms MQ MC MC
Hard, Not applicable for this use NS NS NS NS
SC/L w 157 W 157 * NS NS NS NS NS NS
SC/L W 456 W 456 * NS NS NS NS NS NS
SC/L W 462 W 462 * NS NS NS NS NS NS
Surface treatment. Not on label, Not on SC/L W 154 W 154 * NS NS NS MS MQ MO
label, Hard, Not applicable for this use NS
SC/L w 157 W 157 * NS NS NS NS NS NS
SC/L " 456 W 456 * NS NS NS NS NS NS
SC/L W 462 W 462 * NS NS NS NS NS NS
'
Disallowed Limitations
Codes
A08,
C04,
A08,
C04,
A08,
C04,
A08,
C04,
A08,
C04,
A08,
C04,
A08,
C04,
A08,
C04,
AIO(IO), A40,
C16, CSB, CSD
AIO(IO) , A40,
C16, CSB, CSD
AIO(IO) , A40,
C16, CSB, CSD
AIO(IO) , A40,
C16, CSB, CSP
AIO(IO) , A40,
C16, CSB, CSP
AIO(IO), A40,
C16, CSB, CSD
A10UO), A40,
C16, CSB, CSD
AIO(IO) , A40,
C16, CSB, CSD
Animal feeding/watering equipment
treatment, Not on label, Not on label,
Hard, Not applicable for this use
SC/L W 154
SC/L W 157
SC/L W 456
tfee <3££niJ>: IKBOOft M
W 154 * NS NS
W 157 * NS NS
W 456 * NS NS
NS NS NS NS
NS NS NS NS
NS NS NS NS
A08, AIO(IO), A40,
C04, C16, CSB, CSD
A08, AIO(IO), A40,
C04, C16, CSB, CSD
A08, AIO(IO), A40,
C04, C16, CSB, CSD
-------
Case 3038[Chlorhexidine derivs.l
Chemical 045502[Chlorhexidine diacetate]
SITE Application Type, Application
Timing, Application Equipment -
Surface Type (Antimicrobial only) & Effica-
cy Influencing Factor (Antimicrobial only)
Form(s) Min. Appl.
Rate (AI un-
less noted
otherwise)
Max. Appl. Soil Max. I Apps Max. Dose I(AI Min. Restr. Geographic Limitations Use
Rate (AI Tex. 9 Max. Rate unless noted Interv Entry Allowed Disallowed Limitations
(days) Interv Codes
Iday(s))
unless noted Max. /crop /year otherwise)/A]
otherwise) Dose cycle /crop /year
cycle
NON-FOOD/NON-FEED (con't)
SC/L,
Surface treatment, Not on label, Not on SC/L
label, Hard, Not applicable for this use
SC/L
SC/L
E8G HKNOLINS EQUIPMENT (COMMERCIAL)
Fog, Not on label, Fogger, Hard, Not
applicable foi this use
Soak, Not on label, Not on label, Hard,
Not applicable for this use
Fog, Not on label, Fogger, Hard, Not
applicable for this use
Surface treatment, Not on label, Not on
label, Hard, Not applicable 'for this use
EGG PACKING PLftNTS (COMMERCIAL)
Fog, Not on label, Fogger, Hard, Not
applicable for this use
SC/L.
SC/L
SC/L
SC/L
SC/L
SC/L
W 462
W 154
W 157
W 456
W 462
W 157
W 157
W 157
W 157
W 157
Group< INDOOR NON-POOB
NS NS
NS
W 462
W 154 * NS NS
W 157 * NS NS
W 456 * NS NS
W 462 * NS NS NS
Usss Groups INDOOR NON^FOOD
W 157 * NS NS NS
NS
NS
NS
W 157 » NS NS
NS
Usa Groups INDOOR NON-POOD
W 157 * NS NS NS
W 157 * NS NS
NS
Use Groups INDOOR HOT-FOOD
W 157 * NS NS NS
NS NS
NS NS
NS NS
NS NS
NS NS
NS NS
NS NS
NS NS
NS NS
NS NS
NS
NS
NS
NS
NS
NS
NS
A08,
C04,
A08,
C04,
A08,
C04,
A08,
C04,
A08,
C04,
AIO(IO), A40,
C16, CSB, CSP
A10I10), A40,
C16, CSB, CSD
AIO(IO), A40,
C16, CSB, CSD
AIO(IO), A40,
Clfi, CSB, CSD
A10I10), A40,
C16, CSB, CSD
A06, A08, AIO(IO),
A40, C17
A06, A08, AIO(IO),
A40, C17
A08, AIO(IO), A40,
C17
A08, AIO(IO), A40,
C17
A08, AIO(IO), A40,
C17
29
-------
APPENDIX A REPORT
Case 3038IChlorhexidine derivs.J
Chemical 045S02 (Chlorhexidine diacer.atel
SITE Application Type, Application Form(s) Min. Appl Max ADD! Soil MSy • » Z ^! ', ~=
Timing, Application Equipment - Rate (Aj un. Rat-P IAT T»V a u' D ,' * (AI Min' Restr- Geographic
ysjsjissrsajsa,:,^- SMS -SIKS si si '"'•' E"'":;S, ls" S, ,A"°""
cycle
s Use
owed Limitations
Codes
NON-FOOD/NON-FEED (con't)
ESC PACKING PLftOTS (CQWKBReiAW icoa't)
Surface treatment. Not on label, Not on SC/L W 157
label, Hard, Not applicable for this use
HOSPITALS/MEDICAL- INSTITOTIOSS PREMISES {HUMAN/ VETERINARY}
Animal feeding/watering equipment SC/L
treatment, Not on label, Not on label,
Hard, Not applicable for this use
SC/L
SC/L
SC/L
Immersion, Not on label, Not on label, SC/L
Hard, Not applicable for this use
SC/L
SC/L
SC/L
Surface treatment, Not on label, Not on SC/L
label, Hard, Not applicable for this use
SC/L
W 154
W 157
W 456
W 462
W 154
W 157
W 456
W 462
W 154
W 157
Use Group: INDOOR f
W 157 * NS NS
UB$ Groups INDOOR
W 154 * NS NS
NS NS NS NS
NS NS NS NS
W 157
W 456
W 462
W 154
W 157
W 456
W 462
W 154
W 157
* NS
* NS
* NS
* NS
* NS
* NS
* NS
* NS
* NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
A08, AIO(IO), A40,
C17
A08, AlO-flO), A40,
C04, C16, CSB, CSD
A08,
C04,
A08,
C04,
A08,
C04,
A08,
CD4,
A08,
C04,
A08,
C04,
A08,
C04,
A08,
C04,
A08,
C04,
AIO(IO), A40,
C16, CSB, CSD
A10I10), A40,
cie, CSB, rsn
, AUK 10), A40,
, C16, CSB, CSD
, AIO(IO), A40,
i CIS, CSB, CSD
AIO(IO), A40,
C16, CSB, CSD
AIO(IO), A40,
C16, CSB, CSD
AIO(IO), A40,
C16, CSB, CSD
AIO(IO), A40,
C16, CSB, CSD
AIQ(IO), A40,
C16, CSB, CSD
-------
Case 3038(Chlorhexidine derivs.l
Chemical 045502 IChlorhexidirio
SITE Application Type, Application Form(s) Min. Appl. Max. Appl. Soil Max. I Apps Max. Dose | (AI Min. Restr. Geographic Limitations Use
Timing, Application Equipment - Rate (AI un- Rate (AI Tex. 0 Max. Rate unless noted Interv Entry Allowed Disallowed Limitations
Surface Type (Antimicrobial only) & Effica- less noted unless noted Max. /crop /year othetvise)/A] (days) Interv Codes
cy Influencing Factor (Antimicrobial only) otherwise) otherwise) Dose cycle /crop /year Idaylsll
NON-FOOD/NON-FEED (con't)
p^
SC/L W 456
SC/L
HEftT PROCESSING PlASifT SHIPMENT (FOOD.
Fog, Not on label, Fogger, Hard, Not SC/L
applicable for this use
Soak, Not on label, Not on label, Hard, SC/L
Not applicable tor this use
CONTACT!
SC/L
Fog, Not on label, Fogger, Hard, Not
applicable for this use
Surface treatment. Not on label. Not on SC/L
label. Hard, Not applicable for this use
PROCESSING PtSHT?
tFQOU
Fog, Not on label, Fogger, Hard, Not
applicable for this use
Soak, Not on label, Not on label, Hard,
Not .applicable for this use
SC/L
SC/L
W 462
W 157
W 157
W 157
W 157
W 157
W 157
SC/L W 157
Fog, Not on label, Fogger, Hard, Not
applicable for this use
Surface treatment. Not on label, Not on SC/L
label. Hard, Not applicable for this use
W 157
use orowpi INDOOR
W 456 * NS NS NS
W 462 * NS NS
NS
INDOOR NCJJ-POOO
W 157 * NS NS NS
W 157 * NS NS
NS
Use Groupi INDOOR NON-POOD
W 157 * NS NS NS
W 157 * NS NS NS
Use OSOUp: INDOOR (JOji^POOB
W 157 * NS NS NS
W 157 * NS NS
W 157 * NS NS
W 157 * NS NS
NS
NS NS NS
NS NS NS
NS NS NS
NS NS NS
NS NS NS
NS NS NS
NS NS NS
NS NS NS
NS NS NS NS
NS NS NS NS
A08, AIO(IO), A40,
C04, C16, CSB, CSD
A08, AIO(IO), A40,
C04, ci6, CSB, csn
A06, A08, AIO(IO) ,
A40, C17
A06, A08, A10(10|,
A40, C17
A08, A10(10), A40,
C17
A08, AIO(IO), A40,
C17
A06, A08, AIO(IO),
A40, C17
A06, A08, AIO(IO),
A40, C17
A08, AIO(IO), A40,
C17
A08, AIO(IO), A40,
C17
31
-------
APPENDIX A REPORT
Case 3038(Chlorhexidine derivs.]
Chemical 045502IChlorhexldine dlacetate)
LEGEND
^^
Cycle or per Vear, Minimu, Interval Between Applications (Day*,,
HEADER ABBREVIATIONS
Min. Appl . Rate (AI unless
noted otherwise)
Max. Appl. Rate (AI unless
noted otherwise)
Soil Tex. Max. Dose
Max. » Apps @ Max. Rate
Max. Dose I (AI unless
noted otherwise) /AI
Min. Interv (days)
Restr. Entry Interv (days)
PRO Report Date
Oroup Name Alpha Application Type/Timing/Equipment
Minimum dose for a single application to a single site. System calculated. Microbial claims only.
Maximum dose for a single application to a single site. System calculated.
Maximum dose for a single application to a single site as related to soil texture (Herbicide claims onlvl
^r.nxpre^ed^^M/ryr.31 ""*"» ^ ^ E"-'1" "" •"»«««• Per'year'ls'expr'ess'e^s -4,1 yr"; M applications per 3
Maximum dose applied to a site over a single crop cycle or year. System calculated.
Minimum Interval between Applications (days)
Restricted Entry Interval (days)
^^
SOIL TEXTURE FOR MAX APP. RATE
* Non-specific
C Coarse
M Medium
F Fine
O Others
FORMULAT ON CODES
SC/L SOLUBLE CONCENTRATE/LIQUID
ABBREVIATIONS
AN
NA
NS
UC
As Needed
Not Applicable
Not Specified (on label)
parts, pellets, piece, pieces, pill, pumps, sec, sec burst,' sheet
*"
talt ^^ ^ *^ionls> . bloc*, bri.uet,
APPLICATION RATE
DCNC
No Calc
W
V
U
cwt
nnE-xx
Dosage Can Not be Calculated
No Calculation can be made
PPM calculated by weight
PPM Calculated by volume
Unknown whether PPM is given by weight or by volume
Hundred Weight
nn times (10 power -xx); for instance, "1.234E-04" is equivalent to
1.0001234'
USE LIMITATIONS CODES
A06 : Potable water rinse (non-residual claim).
-------
Report Run Date: 10/05/95 - Time 11:18
LUIS 2.2 - Page:
APPENDIX A REPORT
Case 3038(Chlorhexidine derivs.l
Chemical 045502[Chlorhexidine diacetate!
USE LIMITATIONS CODES (Cont.)
Preclean claim.
minute(s) contact time.
For animal use premises only.
Proper ventilation required.
Remove food and animals from premises prior to treatment.
Remove or carefully protect food products and food packaging.
Do not house poultry, or other animals or employ equipment until treatment has been absorbed, set or dried.
Thoroughly scrub treated feed racks, troughs, automatic feeders, fountains, and waterers with soap or detergent, and rinse with potable water before reuse.
33
-------
GUIDE TO APPENDIX B
Appendix B contains listings of data requirements which support the ^registration for active
ingredients within the case Chloehexidine diacetate covered by this Reregistration Eligibility
Decision Document. It contains generic data requirements that apply to Chloehexidine
diacetate in all products, including data requirements for which a "typical formulation" is the
test substance.
The data table is organized in the following format:
1. Data Requirement (Column 1). The data requirements are listed in the order in
which they appear in 40 CFR Part 158. the reference numbers accompanying each test refer
to the test protocols set in the Pesticide Assessment Guidelines, which are available from the
487 4650 mCai Information Service' 5285 port Royal Road, Springfield, VA 22161 (703)
2. Use Pattern (Column 2). This column indicates the use patterns for which the data
requirements apply. The following letter designations are used for the given use patterns:
A Terrestrial food
B Terrestrial feed
C Terrestrial non-food
D Aquatic food
E Aquatic non-food outdoor
F Aquatic non-food industrial
G Aquatic non-food residential
H Greenhouse food
I Greenhouse non-food
J Forestry
K Residential
L Indoor food
M Indoor non-food
N Indoor medical
O Indoor residential
3- Bibliographic citation (Column 3). If the Agency has acceptable data in its files
this column lists the identifying number of each study. This normally is the Master Record
Identification (MRID) number, but may be a "GS" number if no MRID number has been
assigned. Refer to the Bibliography appendix for a complete citation of the study
34
-------
Data Supporting Guideline Requirements for the Reregistration of Chlorhexidine Diacetate
REQUIREMENT
USE PATTERN
CITATION(S)
PRODUCT CHEMISTRY
61-1
61-2A
61-2B
62-1
62-2
62-3
63-2
63-3
63-4
63-5
63-6
63-7
63-8
63-9
63-10
63-11
63-12
63-13
63-14
Chemical Identity
Start. Mat. & Mnfg. Process
Formation of Impurities
Preliminary Analysis
Certification of limits
Analytical Method
Color
Physical State
Odor
Melting Point
Boiling Point
Density
Solubility
Vapor Pressure
Dissociation Constant
Octanol/Water Partition
pH
Stability
Oxidizing/Reducting Action
ALL
ALL
ALL
ALL
ALL
ALL
ALL
ALL
ALL
ALL
ALL
ALL
ALL
ALL
ALL
ALL
ALL
ALL
ALL
42459901
42459901
42459901
42459902
42459902
42459902
42468001
42468001
42468001
42468001
N/A
42468001
42468001
N/A
N/A
N/A
42468001
42468001
42468001
35
-------
Data Supporting Guideline Requirements for the Reregistration
Kliy U1KEMKIN T
63-15 Flammability
63-16 Explodability
63-17 Storage Stability
63-18 Viscosity
63-19 Miscibility
63-20 Corrosion Characteristics
63-21 Dielectric Breakdown Volt
ECOLOGICAL EFFECTS
71-1A Acute Avian Oral - Quail/Duck
71-2A Avian Dietary - Quail
71-2B Avian Dietary - Duck
72-1A Fish Toxicity Bluegill
72-1C Fish Toxicity Rainbow Trout
72-2A Invertebrate Toxicity
TOXICOLOGY
81-1 Acute Oral Toxicity - Rat
81-2 Acute Dermal Toxicity -
Rabbit/Rat
81-3 Acute Inhalation Toxicity - Rat
81-4 Primary Eye Irritation - Rabbit
81-5 Primary Dermal Irritation - Rabbit
USE PATTERN
=—«—•»•«=•
ALL
ALL
ALL
ALL
ALL
ALL
ALL
ALL
ALL
ALL
ALL
ALL
ALL
ALL
ALL
ALL
ALL
ALL
Diacetate
^^BB^BSB
CITATION(S)
N/A
42468001
42468001
N/A
N/A
42468001
N/A
42197501
42197502
42197503
42197505
42197504
42197506
42706701
42706702
42684201
42706704
42706705
36
-------
cmy|im nug VTUIUCIIIIC jxcuuiiemcius lui me ivci egisiraiiun ui Vxiuurilcxiuillc
REQUIREMENT USE PATTERN
81-6
81-7
82-1A
82-1B
82-2
82-3
83-3A
84-2A
84-2B
84-4
Dermal Sensitization - Guinea Pig
Acute Delayed Neurotoxicity - Hen
90-Day Feeding - Rodent
90-Day Feeding - Non-rodent
21-Day Dermal - Rabbit/Rat
90-Day Dermal - Rodent
Developmental Toxicity - Rat
Gene Mutation (Ames Test)
Structural Chromosomal
Aberration
Other Genotoxic Effects
ALL
ALL
ALL
ALL
ALL
ALL
ALL
ALL
ALL
ALL
CITATION(S)
42706706
WAIVED
WAIVED
WAIVED
WAIVED
40952201
42102101
40231005
40231004
40231003
OCCUPATIONAL/RESIDENTIAL EXPOSURE
233 Estimation of Dermal Exposure at ALL 41412201,41742601,42587501
Indoor Sites
234 Estimation of Inhalation Exposure ALL 41412201,41742601,42587501
at Indoor Sites
ENVIRONMENTAL FATE
160-5 Chemical Identity ALL 42459901
37
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GUIDE TO APPENDIX C
1. CONTENTS OF BIBLIOGRAPHY. This bibliography contains citations of all studies
considered relevant by EPA in arriving at the positions and conclusions stated
elsewhere in the Reregistration Eligibility Document. Primary sources for studies in
this bibliography have been the body of data submitted to EPA and its predecessor
agencies in support of past regulatory decisions. Selections from other sources
including the published literature, in those instances where they have been considered
are included. '
2. UNITS OF ENTRY. The unit of entry in this bibliography is called a "study" In the
case of published materials, this corresponds closely to an article. In the case of
unpublished materials submitted to the Agency, the Agency has sought to identify
documents at a level parallel to the published article from within the typically larger
volumes in which they were submitted. The resulting "studies" generally have a
distinct title (or at least a single subject), can stand alone for purposes of review and
can be described with a conventional bibliographic citation. The Agency has also
attempted to unite basic documents and commentaries upon them, treating them as a
single study.
3. IDENTIFICATION OF ENTRIES. The entries in this bibliography are sorted
numerically by Master Record Identifier, or "MRID number". This number is unique
to the citation, and should be used whenever a specific reference is required It is not
related to the six-digit "Accession Number" which has been used to identify volumes of
submitted studies (see paragraph 4(d)(4) below for further explanation). In a few
cases, entries added to the bibliography late in the review may be preceded by a nine
character temporary identifier. These entries are listed after all MRID entries This
temporary identifying number is also to be used whenever specific reference is needed.
4. FORM OF ENTRY. In addition to the Master Record Identifier (MRID), each entry
consists of a citation containing standard elements followed, in the case of material
submitted to EPA, by a description of the earliest known submission. Bibliographic
conventions used reflect the standard of the American National Standards Institute
(ANSI), expanded to provide for certain special needs.
a Author. Whenever the author could confidently be identified, the Agency has
chosen to show a personal author. When no individual was identified, the
Agency has shown an identifiable laboratory or testing facility as the author.
When no author or laboratory could be identified, the Agency has shown the
first submitter as the author.
b. Document date. The date of the study is taken directly from the document.
When the date is followed by a question mark, the bibliographer has deduced
the date from the evidence contained in the document. When the date appears
as (19??), the Agency was unable to determine or estimate the date of the
document.
38
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c. Title. In some cases, it has been necessary for the Agency bibliographers to
create or enhance a document title. Any such editorial insertions are contained
between square brackets.
d. Trailing parentheses. For studies submitted to the Agency in the past, the
trailing parentheses include (in addition to any self-explanatory text) the
following elements describing the earliest known submission:
(1) Submission date. The date of the earliest known submission appears
immediately following the word "received."
(2) Administrative number. The next element immediately following the
word "under" is the registration number, experimental use permit
number, petition number, or other administrative number associated
with the earliest known submission.
(3) Submitter. The third element is the submitter. When authorship is
defaulted to the submitter, this element is omitted.
(4) Volume Identification (Accession Numbers). The final element in the
trailing parentheses identifies the EPA accession number of the volume
in which the original submission of the study appears. The six-digit
accession number follows the symbol "CDL," which stands for
"Company Data Library." This accession number is in turn followed by
an alphabetic suffix which shows the relative position of the study within
the volume.
39
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BIBLIOGRAPHY
MRID
CITATION
00058615
00063591
40230903
40230904
40230905
40231001
40231002
40231003
40231004
40231005
Foulkes, D.M. (1973) Some lexicological observations on Chlorhexidine
Journal of Periodontal Research 8(Suppl. 12):55-57. (Also In unpublished
submission received Feb 20, 1981 under 2097-12; submitted by Beecham
Laboratories, Bristol, Tenn.; CDL:244436-D)
Fort Dodge Laboratories (1955) Experiments, Clinical Trials Indicating Safety
(Unpublished study received Jun 6, 1955 under unknown admin no •
CDL:110210-A)
Myhr, B. (1983) Primary Rat Hepatocyte Unscheduled DNA Synthesis Assay
Chlorhexidme Hydrochloride: Final Report. Unpublished study prepared bv
Litton Bionetics, Inc. 15 p.
Farrow, M. (1983) In-vitro Chromosome Aberrations in Chinese Hamster
Ovary Cells Assay with Chlorhexidine Hydrochloride: Final Report: Hazleton
Project No. 2191-101. Unpublished study prepared by Hazleton Laboratories
America. 24 p.
Cifone, M. (1984) Mouse Lymphoma Forward Mutation Assay: Chlorhexidine
Hydrochloride: LBI Project No. 20989. Unpublished study prepared by Litton
Bionetics, Inc. 24 p.
Kuzdas, C.; Frinch, R.(1980) Ames-Salmonella/Microsome Mutagenicity
Test: Chlorhexidine Diacetate: Laboratory Project No.: 728366: 748579
Unpublished study prepared by Raltech Scientific Service. 18 p.
Farrow, M. (1982) Mouse Lymphoma Forward Mutation Assay: Chlorhexidine
Hydrochlonde: Hazleton Project No. 2191-100. Unpublished study prepared
by Hazleton Laboratories America. 18 p.
Myhr, B. (1983) Primary Rat Hepatocyte Unscheduled DNA Synthesis Assay
Chlorhexidine Hydrochloride: LBI Project No. 20991. Unpublished study
prepared by Litton Bionetics, Inc. 15 p.
Farrow, M. (1983) In-vitro Chromosome Aberrations in Chinese Hamster
Ovary Cells Assay: Chlorhexidine Hydrochloride: Hazleton Project No.
2191-101. Unpublished study prepared by Hazleton Laboratories America 24
P-
Cifone, M. (1984) Mouse Lymophoma Forward Mutation Assay: Chlorhexidine
Hydrochloride: LBI Project No. 20989. Unpublished study prepared by Litton
Bionetics, Inc. 24 p.
40
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BIBLIOGRAPHY
MRID
CITATION
40231103 Myhr, B. (1983) Primary Rat Hepatocyte Unscheduled DNA Synthesis Assay
Using Chlorhexidine Hydrochloride: LSI Project No. 20991. Unpublished
study prepared by Litton Bionetics, Inc. 15 p.
40853001 Kenwood, S. (1988) Range-finding Teratology Study with Chlorhexidine .
Acetate in Rats: Final Report: Laboratory Project ID: HLA 6247-100.
Unpublished study prepared by Hazleton Laboratories America, Inc. 55 p.
40853101 Kenwood, S. (1988) Range-finding Teratology Study with Chlorhexidine
Acetate in Rats: Final Report: Laboratory Project ID: HLA 6247-100.
Unpublished study prepared by Hazleton Laboratories America, Inc. 55 p.
40853201 Kenwood, S. (1988) Range-finding Teratology Study with Chlorhexidine
Acetate in Rats: Laboratory Project ID HLA 6247-100. Unpublished study
prepared by Hazleton Laboratories America, Inc. 55 p.
40952201 Kenwood, S. (1988) 13-Week Dermal Toxicity Study with Chlorhexidine
Acetate in Rabbits: Final Report: Laboratory Project ID HLA 6247-102.
Unpublished study prepared by Hazleton Laboratories America, Inc. 283 p.
40964201 Kenwood, S. (1988) Teratology Study with Chlorhexidine Acetate in Rats:
Laboratory Project ID HLA 6247-101. Unpublished study prepared by
Hazleton Laboratories America, Inc. 179 p.
42102101 Lamb, I. (1991) A Developmental Toxicity Study of Chlorhexidine Diacetate in
Rats: Final Report: Lab Project Number: WIL-173001. Unpublished study
prepared by WIL Research Labs. 361 p.
42197501 Campbell, S.; Grimes, J.; Smith, G.; et al. (1991) Chlorhexidine Diacetate:
An Acute Oral Toxicity Study with the Northern Bobwhite: Lab Project
Number: 277-103. Unpublished study prepared by Wildlife Interntional, Ltd
20 p.
42197502 Long, R.; Hoxter, K.; Smith, G.; et al. (1991) Chlorhexidine Diacetate: A
Dietary LC50 Study with the Northern Bobwhite: Lab Project Number:
277-101. Unpublished study prepared by Wildlife International, Ltd. 26 p.
42197503 Long, D.; Hoxter, K.; Smith, G.; et al. (1991) Chlorhexidine Diacetate: A
Dietary LC50 Study With The Mallard: Lab Project Number: 277-102.
Unpublished study prepared by Wildlife International, Ltd. 25 p.
42197504 Murphy, D.; Smith, G. (1991) Chlorhexidine Diacetate: A 96-Hour Static
Acute Toxicity Test With The Rainbow Trout (Oncorhynchus Mykiss): Lab
41
-------
BIBLIOGRAPHY
MRID
CITATION
Project Number: 277A-101. Unpublished study prepared by Wildlife
International, Ltd. 28 p.
42197505
42197506
42442601
42442701
42459901
42459902
42468001
42633201
42684201
42706701
Murphy, D.; Smith, G. (1991) Chlorhexidine Diacetate: A 96-Hour Static
Acute Toxicity Test With The Bluegill (Lepomis Macrochirus): Lab Project
Number: 277A-102. Unpublished study prepared by Wildlife International,
Ltd. 28 p.
Murphy, D.; Smith, G. (1991) Chlorhexidine Diacetate: A 48-Hour Static
Acute Toxicity Test With The Cladoceran (Daphnia Magna): Lab Project
Number: 227A-103. Unpublished study prepared by Wildlife International
Ltd. 29 p. '
Wood, C. (1991) Freeze/Thaw Study for Nolvasan-S: Lab Project Number
3639. Unpublished study prepared by Fort Dodge Laboratories. 13 p.
Wood, C. (1992) Freeze/Thaw Study for Nolvasan Solution: Lab Project
Number: 3655. Unpublished study prepared by Fort Dodge Laboratories 13
P-
Walzer, E. (1992) Chlorhexidine Diacetate (CHDAC): Product Identity and
Composition. Unpublished study prepared by Degussa AG. 18 p.
Walzer, E. (1992) Chlorhexidine Diacetate (CHDAC): Analysis and.
Certification of Product Ingredients. Unpublished study prepared by Degussa
AG. 30 p.
Walzer, E. (1992) Chlorhexidine Diacetate (CHAC): Physical and Chemical
Characteristics. Unpublished study prepared by Degussa AG. 9 p.
Reagan, E. (1989) Acute Oral Toxicity Study of Chlorhexidine Acetate in
Sprague-Dawley Rats: Lab Project Number: 89.1810.003. Unpublished study
prepared by Food and Drug Research Labs. 77 p.
Shapiro, R. (1993) EPA Acute Inhalation Toxicity-Defined LC50-
Chlorohexidine-Diacetate: Lab Project Number: T-1813. Unpublished study
prepared by Product Safety Labs. 37 p.
Miller, E. (1993) Acute Oral Toxicity Evaluation of Chlorhexidine Diacetate
Technical in Rats: Lab Project Number: 9096-92: P952-1: KVR-P952-1.
Unpublished study prepared by Stillmeadow, Inc. 70 p.
42
-------
BIBLIOGRAPHY
MRID
CITATION
42706702 Miller, E. (1993) Acute Dermal Toxicity Evaluation of Chlorhexidine Diacetate
Technical in Rabbits: Lab Project Number: 9097-92: KVR-P952-2.
Unpublished study prepared by Stillmeadow Inc. 52 p.
42706703 Miller, E. (1993) Acute Inhalation Toxicity Evaluation of Chlorhexidine
Diacetate Technical in Rats: Lab Project Number: 9098-92: KVP-P952-3.
Unpublished study prepared by Stillmeadow Inc. 113 p.
42706704 Miller, E. (1993) Primary Eye Irritation Evaluation of Chlorhexidine Diacetate
Technical in Rabbits: Lab Project Number: 9099-92: KVP-P952-4.
Unpublished study prepared by Stillmeadow Inc. 60 p.
42706705 Miller, E. (1993) Primary Dermal Irritation Evaluation of Chlorhexidine
Diacetate Technical in Rabbits: Lab Project Number: 9100-92:KVR-P952-5.
Unpublished study prepared by Stillmeadow Inc. 50 p.
42706706 Miller, E. (1993) Evaluation of Sensitization Potential of Chlorhexidine
Diacetate Technical in Guinea Pigs: Lab Project Number: 9101-92:
KVP-P952-6. Unpublished study prepared by Stillmeadow Inc. 58 p.
42707001 White, W. (1993) Chlorhexidine Acetate Ph Eur Chemistry and Pharmacy
Data: Lab Project Number: 2/IC/US/1000502. Unpublished study prepared by
Zeneca Pharmaceuticals. 32 p.
43438501 Rhodes, M. (1994) Chlorhexidine Acetate Product Identity. Unpublished study
prepared by Zeneca Pharmaceuticals. 6 p.
43438502 Rhodes, M. (1994) Description of Starting Materials and Manufacturing
Process and Discussion of the Formation of Impurities for Chlorhexidine
Acetate. Unpublished study prepared by Zeneca Pharmaceuticals. 15 p.
43438503 Rhodes, M. (1994) Chlorhexidine Acetate: Preliminary Analysis, Certified
Limits and Analytical Methods. Unpublished study prepared by Zeneca
Pharmaceuticals. 15 p.
43491901 Rhodes, M. (1994) Chlorhexidine Acetate: Physical and Chemical Properties.
Unpublished study prepared by Zeneca Pharmaceuticals. 5 p.
93065001 Kenwood, S. (1990) Fort Dodge Laboratories Phase 3 Summary of MRID
40952201. 13-Week Dermal Toxicity Study with Chlorhexidine Acetate in
Rabbits: HLA 6247-102. Prepared by Hazleton Laboratories America, Inc. 21
P-
43
-------
MRID
BIBLIOGRAPHY
CITATION
93065002
93065003
93065004
93065005
93065006
93065007
93065008
Kenwood, S. (1990) Fort Dodge Laboratories Phase 3 Summary of MRID
40853101. Range-Finding Teratology Study with Chlorhexidine Acetate in
Rats: HLA 6247-100. Prepared by Hazleton Laboratories America, Inc. 19 p.
Kenwood, S. (1990) Fort Dodge Laboratories Phase 3 Summary of MRID
40964201. Teratology Study with Chlorhexidine Acetate in Rats: HLA
6247-101. Prepared by Hazleton Laboratories America, Inc. 28 p.
Kuzdas, C.; Frinch, R. (1990) Fort Dodge Laboratories Phase 3 Summary of
MRID 40230901. Ames-Salmonella/Microsome Mutagenicity Test
#728366,748579, 728367, 748580. Prepared by Raltech Scientific Service 27
P-
Farrow, M. (1990) Fort Dodge Laboratories Phase 3 Summary of MRID
40230904. In-vitro Chromosome Aberrations in Chinese Hamster Ovary Cells
Assay: Project No. 2191-101. Prepared by Hazleton Laboratories America 15
P-
Myhr, B. (1990) Fort Dodge Laboratories Phase 3 Summary of MRID
40230903. Primary Rat Hepatocyte Unscheduled DNA Synthesis Assay-
Project No. 20991. Prepared by Litton Bionetics, Inc. 15 p.
Farrow, M. (1990) Fort Dodge Laboratories Phase 3 Summary of MRID
40230902. Mouse Lymphoma Forward Mutation Assay: Project No.
2191-100. Prepared by Hazleton Laboratories America. 15 p.
Cifone, M. (1990) Fort Dodge Laboratories Phase 3 Summary of MRID
40230905. Mouse Lymphoma Forward Mutation Assay: Project No. 20989
Prepared by Litton Bionetics, Inc. 15 p.
44
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
•
'*U wort-0 WASHINGTON, D.C. 2O46O
omci 01
pcrvnmoi. PMTKIDSA
AID TOHC 4UMTAHCIA
DATA CALL-IN NOTICE
CERTIFIED MAIL
Dear Sir or Madam:
This Notice requires you and other registrants of pesticide products containing the active
ingredient identified in Attachment 1 of this Notice, the Data Call-In Chemical Status Sheet, to
submit certain product specific data as noted herein to the U.S. Environmental Protection
Agency (EPA, the Agency). These data are necessary to maintain the continued registration of
your product(s) containing this active ingredient. Within 90 days after you receive this Notice
you must respond as set forth in Section in below. Your response must state:
1. How you will comply with the requirements set forth in this Notice and its
Attachments 1 through 6; or
2. Why you believe you are exempt from the requirements listed in this Notice and
in Attachment 3, Requirements Status and Registrant's Response Form, (see
section ni-B); or
3. Why you believe EPA should not require your submission of product specific
data in the manner specified by this Notice (see section ni-D).
If you do not respond to this Notice, or if you do not satisfy EPA that you will comply
with its requirements or should be exempt or excused from doing so, then the registration of
your product(s) subject to this Notice will be subject to suspension. We have provided a list of
all of your products subject to this Notice in Attachment 2, Data Call-In Response Form, as
well as a list of all registrants who were sent this Notice (Attachment 6).
The authority for this Notice is section 3(c)(2)(B) of the Federal Insecticide, Fungicide
and Rodenticide Act as amended (FIFRA), 7 U.S.C. section 136a(c)(2)(B). Collection of this
information is authorized under the Paperwork Reduction Act by OMB Approval No. 2070-
0107 and 2070-0057 (expiration date 03-31-96).
45
-------
This Notice is divided into six sections and six Attachments. The Notice itself contains
information and instructions applicable to all Data Call-in Notices. The Attachments contain
specific chemical information and instructions. The six sections of the Notice are:
Section I - Why You Are Receiving This Notice
Section n - Data Required By This Notice
Section IE - Compliance With Requirements Of This Notice
Section IV - Consequences Of Failure To Comply With This Notice
Section V - Registrants' Obligation To Report Possible Unreasonable Adverse
Effects
Section VI - Inquiries And Responses To This Notice
The Attachments to this Notice are:
1 - Data Call-In Chemical Status Sheet
2 - Product-Specific Data Call-In Response Form
3 -. EPA Batching of End-Use Products for Meeting Acute Toxicology Data
Requirements for Reregistration" "
4 - List of Registrants Receiving This Notice
5 - Cost Share and Data Compensation Forms
SECTION I. WHY YOU ARE RECEIVING THIS NOTICE
The Agency has reviewed existing data for this active ingredient and reevaluated the
data needed to support continued registration of the subject active ingredient. The Agency has
concluded that the only additional data necessary are product specific data No additional
generic data requirements are being imposed. You have been sent this Notice because you
have product(s) containing the subject active ingredient.
SECTION II. DATA REQUIRED BY THIS NOTICE
H-A. DATA REQUIRED
The product specific data required by this Notice are specified in Attachment 3,
Requirements Status and Registrant's Response Form. Depending on the results of the studies
required in this Notice, additional testing may be required.
n-B. SCHEDULE FOR SUBMISSION OF DATA
You are required to submit the data or otherwise satisfy the data requirements specified in
Attachment 3, Requirements Status and Registrant's Response Form, within the time frames
provided. ~ '—
46
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H-C. TESTING PROTOCOL
All studies required under this Notice must be conducted in accordance with test standards
outlined in the Pesticide Assessment Guidelines for those studies for which guidelines have been
established.
These EPA Guidelines are available from the National Technical Information Service
(NTIS), Attn: Order Desk, 5285 Port Royal Road, Springfield, Va 22161 (tel: 703-487-4650).
Protocols approved by the Organization for Economic Cooperation and Development
(OECD) are also acceptable if the OECD-recommended test standards conform to those specified
in the Pesticide Data Requirements regulation (40 CFR § 158.70). When using the OECD
protocols, they should be modified as appropriate so that the data generated by the study will
satisfy the requirements of 40 CFR § 158. Normally, the Agency will not extend deadlines for
complying with data requirements when the studies were not conducted in accordance with
acceptable standards. The OECD protocols are available from OECD, 2001 L Street, N.W.,
Washington, D.C. 20036 (Telephone number 202-785-6323; Fax telephone number 202-785-
0350).
All new studies and proposed protocols submitted in response to this Data Call-In Notice
must be in accordance with Good Laboratory Practices [40 CFR Part 160.3(a)(6)].
H-D. REGISTRANTS RECEIVING PREVIOUS SECTION 3(c)(2)(B) NOTICES
ISSUED BY THE AGENCY ~
Unless otherwise noted herein, this Data Call-In does not in any way supersede or change the
requirements of any previous Data Call-In(s), or any other agreements entered into with the
Agency pertaining to such prior Notice. Registrants must comply with the requirements of all
Notices to avoid issuance of a Notice of Intent to Suspend their affected products.
SECTION HI. COMPLIANCE WITH REQUIREMENTS OF THIS NOTICE
m-A. SCHEDULE FOR RESPONDING TO THE AGENCY
The appropriate responses initially required by this Notice for product specific data must
be submitted to the Agency within 90 days after your receipt of this Notice. Failure to adequately
respond to this Notice within 90 days of your receipt will be a basis for issuing a Notice of Intent
to Suspend (NOIS) affecting your products. This and other bases for issuance of NOIS due to
failure to comply with this Notice are presented in Section IV-A and IV-B.
HI-B. OPTIONS FOR RESPONDING TO THE AGENCY
The options for responding to this Notice for product specific data are: (a) voluntary
cancellation, (b) agree to satisfy the product specific data requirements imposed by this notice or
(c) request a data waiver(s).
47
-------
A discussion of how to respond if you chose the Voluntary Cancellation option is
presented below. A discussion of the various options available for satisfying the product specific
data requirements of this Notice is contained in Section HI-C. A discussion of options relating to
requests for data waivers is contained in Section ni-D.
There are two forms that accompany this Notice of which, depending upon your response
one or both must be used in your response to the Agency. These forms are the Data-Call-in
Response Form, and the Requirements Status and Registrant's Response Form, Attachment 2 and
Attachment 3. The Data Call-in Response Form must be submitted as part of every response to
this Notice. In addition, one copy of the Requirements Status and Registrant's Response Form
must be submitted for each product listed on the Data Call-in Response Form unless the voluntary
cancellation option is selected or unless the product is identical to another (refer to the instructions
for completing the Data Call-in Response Form in Attachment 2). Please note that the company's
authorized representative is required to sign the first page of the Data Call-in Response Form and
Requirements Status and Registrant's Response Form (if this form is required) and initial any
subsequent pages. The forms contain separate detailed instructions on the response options. Do
not alter the printed material. If you have questions or need assistance in preparing your
response, call or write the contact person(s) identified in Attachment 1.
1 • Voluntary Cancellation - You may avoid the requirements of this Notice by requesting
voluntary cancellation of your product(s) containing the active ingredient that is the subject of this
Notice. If you wish to voluntarily cancel your product, you must submit a completed Data Call-in
Response Form, indicating your election of this option. Voluntary cancellation is item number 5
on the Data Call-in Response Form. If you choose this option, this is the only form that you are
required to complete.
If you chose to voluntarily cancel your product, further sale and distribution of your
product after the effective date of cancellation must be in accordance with the Existing Stocks
provisions of this Notice which are contained in Section IV-C.
2- Satisfying the Product Specific Data Requirements of this Notice There are various
options available to satisfy the product specific data requirements of this Notice. These options
are discussed in Section IH-C of this Notice and comprise options 1 through 6 on the
Requirements Status and Registrant's Response Form and item numbers 7a and 7b on the Data
CaU-In Response Form. Deletion of a use(s) and the low volume/minor use option are not~vaird
options for fulfilling product specific data requirements.
3. Request for Product Specific Data Waivers. Waivers for product specific data are
discussed in Section HI-D of this Notice and are covered by option 7 on the Requirements Status
and Registrant's Response Form. If you choose one of these options, you must submit both forms
as well as any other information/data pertaining to the option chosen to address the data
requirement.
48
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ffl-C SATISFYING THE DATA REQUIREMENTS OF THIS NOTICE
If you acknowledge on the Data Call-in Response Form that you agree to satisfy the
product specific data requirements (i.e. you select item number 7a or 7b), then you must select
one of the six options on the Requirements Status and Registrant's Response Form related to data
production for each data requirement. Your option selection should be entered under item
number 9, "Registrant Response." The six options related to data production are the first six
options discussed under item 9 in the instructions for completing the Requirements Status and
Registrant's Response Form. These six options are listed immediately below with information in
parentheses to guide registrants to additional instructions provided in this Section. The options
are:
(1) I will generate and submit data within the specified time frame (Developing Data)
(2) I have entered into an agreement with one or more registrants to develop data
jointly (Cost Sharing)
(3) I have made offers to cost-share (Offers to Cost Share)
(4) I am submitting an existing study that has not been submitted previously to the
Agency by anyone (Submitting an Existing Study)
(5) I am submitting or citing data to upgrade a study classified by EPA as partially
acceptable and upgradeable (Upgrading a Study)
(6) I am citing an existing study that EPA has classified as acceptable or an existing
study that has been submitted but not reviewed by the Agency (Citing an Existing
Study)
Option 1, Developing Data - If you choose to develop the required data it must be in
conformance with Agency deadlines and with other Agency requirements as referenced herein and
in the attachments. All data generated and submitted must comply with the Good Laboratory
Practice (GLP) rule (40 CFR Part 160), be conducted according to the Pesticide Assessment
Guidelines (PAG), and be in conformance with the requirements of PR Notice 86-5.
The time frames in the Requirements Status and Registrant's Response Form are the time
frames that the Agency is allowing for the submission of completed study reports. The noted
deadlines run from the date of the receipt of this Notice by the registrant. If the data are not
submitted by the deadline, each registrant is subject to receipt of a Notice of Intent to Suspend the
affected registration(s).
If you cannot submit the data/reports to the Agency in the time required by this Notice and
intend to seek additional time to meet the requirements(s), you must submit a request to the
Agency which includes: (1) a detailed description of the expected difficulty and (2) a proposed
schedule including alternative dates for meeting such requirements on a step-by-step basis. You
must explain any technical or laboratory difficulties and provide documentation from the
laboratory performing the testing. While EPA is considering your request, the original deadline
remains. The Agency will respond to your request in writing. If EPA does not grant your
request, the original deadline remains. Normally, extensions can be requested only in cases of
extraordinary testing problems beyond the expectation or control of the registrant. Extensions
will not be given in submitting the 90-day responses. Extensions will not be considered if the
49
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request for extension is not made in a timely fashion; in no event shall an extension request be
considered if it is submitted at or after the lapse of the subject deadline.
, . Option 2, Agreement to Share in Cost to Develop Data - Registrants may only choose
this option for acute toxicity data and certain efficacy data and only if EPA has indicated in the
attached data tables that your product and at least one other product are similar for purposes of
depending on the same data. If this is the case, data may be generated for just one of the products
in the group. The registration number of the product for which data will be submitted must be
noted in the agreement to cost share by the registrant selecting this option. If you chooielS enter
into an agreement to share in the cost of producing the required data but will not be submitting
the data yourself, you must provide the name of the registrant who will be submitting the data
You must also provide EPA with documentary evidence that an agreement has been formed Such
evidence may be your letter offering to join in an agreement and the other registrant's acceptance
of your offer, or a written statement by the parties that an agreement exists. The agreement to
produce the data need not specify all of the terms of the final arrangement between the parties or
the mechanism to resolve the terms. Section 3(c)(2)(B) provides that if the parties cannot resolve
the terms of the agreement they may resolve their differences through binding arbitration.
ar t t Option 3 Offer to Share in the Cost of Data Development - This option only applies to
ff* toxicity and certain ethcacy data as described in option 2 above. If you have made an offer
to pay in an attempt to enter into an agreement or amend an existing agreement to meet the
requirements of this Notice and have been unsuccessful, you may request EPA (by selecting this
2X,Th HetXerCK6 lts.discreuon not to «»I*nd your registration(s), although you do not comply
wuh the data submission requirements of this Notice. EPA has determined that as a general
policy, absent other relevant considerations, it will not suspend the registration of a product of a
registrant who has in good faith sought and continues to seek to enter into a joint data
ac'cetCroffrr ^ ^°g,ram'v,bUt ^ 0thCr reSistran«s> developing the data has refused to
accept your offer To qualify for this option, you must submit documentation to the Agency
fnTr8 ly°K HVC T^ "? °ffer t0 another registrant (who has ™ obligation <° submit data)
EPA For^ *™Tvnr d?eloPm&^ data' You ™<" also submit to the Agency a completed
7 t ,T, ' CerUf1Catl0n of Offer to Cost Share in the Development of Data, Attachment
7 In addition, you must demonstrate that the other registrant to whom the offer was made has
not accepted your offer to enter into a cost sharing agreement by including a copy of your offer
and proof of the other registrant's receipt of that offer (such as a certified mail receipt) Your
offer must, in addition to anything else, offer to share in the burden of producing the data upon
SnnV^AvSr-f ^ agreement to be bound bv binding arbitration as provided by FIFRA
section 3(c)(2)(B)(m) and must not qualify this offer. The other registrant must also inform EPA
of its election of an option to develop and submit the data required by this Notice by submitting a
Data Call-in Response Form and a Requirements Status and Registrant's Response Form
committing to develop and submit the data required by this Notice. "
In order for you to avoid suspension under this option, you may not withdraw your offer
to share in the burdens of developing the data. In addition, the other registrant must fulfill its
commitment to develop and submit the data as required by this Notice. If the other registrant fails
to develop the data or for some other reason is subject to suspension, your registration as well as
that of the other registrant will normally be subject to initiation of suspension proceedings unless
50
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you commit to submit, and do submit the required data in the specified time frame. In such cases,
the Agency generally will not grant- a time extension for submitting the data.
Option 4, Submitting an Existing Study — If you choose to submit an existing study in
response to this Notice, you must determine that the study satisfies the requirements imposed by
this Notice. You may only submit a study that has not been previously submitted to the Agency
or previously cited by anyone. Existing studies are studies which predate issuance of this Notice.
Do not use this option if you are submitting data to upgrade a study. (See Option 5).
You should be aware that if the Agency determines that the study is not acceptable, the
Agency will require you to comply with this Notice, normally without an extension of the
required date of submission. The Agency may determine at any time that a study is not valid and
needs to be repeated.
To meet the requirements of the DCI Notice for submitting an existing study, all of the
following three criteria must be clearly met:
a. You must certify at the time that the existing study is submitted that the raw data
and specimens from the study are available for audit and review and you must
identify where they are available. This must be done in accordance with the
requirements of the Good Laboratory Practice (GLP) regulation, 40 CFR Part 160.
As stated in 40 CFR 160.3(j) " 'raw data' means any laboratory worksheets,
records, memoranda, notes, or exact copies thereof, that are the result of original
observations and activities of a study and are necessary for the reconstruction and
evaluation of the report of that study. In the event that exact transcripts of raw
data have been prepared (e.g., tapes which have been transcribed verbatim, dated,
and verified accurate by signature), the exact copy or exact transcript may be
substituted for the original source as raw data. 'Raw data1 may include
photographs, microfilm or microfiche copies, computer printouts, magnetic media,
including dictated observations, and recorded data from automated instruments."
The term "specimens", according to 40 CFR 160.3(k), means "any material
derived from a test system for examination or analysis."
b. Health and safety studies completed after May 1984 must also contain all GLP-
required quality assurance and quality control information, pursuant to the
requirements of 40 CFR Part 160. Registrants must also certify at the time of
submitting the existing study that such GLP information is available for post-May
1984 studies by including an appropriate statement on or attached to the study
signed by an authorized official or representative of the registrant.
c. You must certify that each study fulfills the acceptance criteria for the Guideline
relevant to the study provided in the FIFRA Accelerated Reregistration Phase 3
Technical Guidance and that the study has been conducted according to the
Pesticide Assessment Guidelines (PAG) or meets the purpose of the PAG (both
available from NTIS). A study not conducted according to the PAG may be
submitted to the Agency for consideration if the registrant believes that the study
clearly meets the purpose of the PAG. The registrant is referred to 40 CFR 158.70
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which states the Agency's policy regarding acceptable protocols. If you wish to
submit the study, you must, in addition to certifying that the purposes of the PAG
are met by the study, clearly articulate the rationale why you believe the study
meets the purpose of the PAG, including copies of any supporting information or
data. It has been the Agency's experience that studies completed prior to January
1970 rarely satisfied the purpose of the PAG and that necessary raw data are
usually not available for such studies.
If you submit an existing study, you must certify that the study meets all requirements of
the criteria outlined above.
If you know of a study pertaining to any requirement in this Notice which does not meet
the criteria outlined above but does contain factual information regarding unreasonable adverse
effects, you must notify the Agency of such a study. If such study is in the Agency's files, you
need only cite it along with the notification. If not in the Agency's files, you must submit a
summary and copies as required by PR Notice 86-5.
Option 5. Upgrading a Study - If a study has been classified as partially acceptable and
upgradeable, you may submit data to upgrade that study. The Agency will review the data
submitted and determine if the requirement is satisfied. If the Agency decides the requirement is
not satisfied, you may still be required to submit new data normally without any time extension
Deficient, but upgradeable studies will normally be classified as supplemental. However, it is
important to note that not all studies classified as supplemental are upgradeable. If you have
questions regarding the classification of a study or whether a study may be upgraded, call or write
the contact person listed in Attachment 1. If you submit data to upgrade an existing study you
must satisfy or supply information to correct all deficiencies in the study identified by EPA You
must provide a clearly articulated rationale of how the deficiencies have been remedied or
corrected and why the study should be rated as acceptable to EPA. Your submission must also
specify the MRID number(s) of the study which you are attempting to upgrade and must be in
conformance with PR Notice 86-5.
Do not submit additional data for the purpose of upgrading a study classified as
unacceptable and determined by the Agency as not capable of being upgraded.
This option should also be used to cite data that has been previously submitted to upgrade
a study, but has not yet been reviewed by the Agency. You must provide the MRID number of
the data submission as well as the MRID number of the study being upgraded.
The criteria for submitting an existing study, as specified in Option 4 above, apply to all
data submissions intended to upgrade studies. Additionally your submission of data intended to
upgrade studies must be accompanied by a certification that you comply with each of those
criteria as well as a certification regarding protocol compliance with Agency requirements.
Option 6, Citing Existing Studies - If you choose to cite a study that has been previously
submitted to EPA, that study must have been previously classified by EPA as acceptable or it
must be a study which has not yet been reviewed by the Agency. Acceptable toxicology studies
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generally will have been classified as "core-guideline" or "core minimum." For all other
disciplines the classification would be "acceptable." With respect to any studies for which you
wish to select this option you must provide the MRID number of the study you are citing and, if
the study has been reviewed by the Agency, you must provide the Agency's classification of the
study.
If you are citing a study of which you are not the original data submitter, you must submit
a completed copy of EPA Form 8570-31, Certification with Respect to Data Compensation
Requirements.
Registrants who select one of the above 6 options must meet all of the requirements
described in the instructions for completing the Data Call-in Response Form and the Requirements
Status and Registrant's Response Form, as appropriate.
m-D REQUESTS FOR DATA WAIVERS
If you request a waiver for product specific data because you believe it is
inappropriate, you must attach a complete justification for the request, including technical
reasons, data and references to relevant EPA regulations, guidelines or policies. (Note: any
supplemental data must be submitted in the format required by PR Notice 86-5). This will be the
only opportunity to state the reasons or provide information in support of your request. If the
Agency approves your waiver request, you will not be required to supply the data pursuant to
section 3(c)(2)(B) of FIFRA. If the Agency denies your waiver request, you must choose an
option for meeting the data requirements of this Notice within 30 days of the receipt of the
Agency's decision. You must indicate and submit the option chosen on the Requirements Status
and Registrant's Response Form. Product specific data requirements for product chemistry, acute
toxicity and efficacy (where appropriate) are required for all products and the Agency would grant
a waiver only under extraordinary circumstances. You should also be aware that submitting a
waiver request will not automatically extend the due date for the study in question. Waiver
requests submitted without adequate supporting rationale will be denied and the original due date
will remain in force.
IV. CONSEQUENCES OF FAILURE TO COMPLY WITH THIS NOTICE
IV-A NOTICE OF INTENT TO SUSPEND
The Agency may issue a Notice of Intent to Suspend products subject to this Notice due to
failure by a registrant to comply with the requirements of this Data.Call-In Notice, pursuant to
FIFRA section 3(c)(2)(B). Events which may be the basis for issuance of a Notice of Intent to
Suspend include, but are not limited to, the following:
1. Failure to respond as required by this Notice within 90 days of your receipt of this
Notice.
2. Failure to submit on the required schedule an acceptable proposed or final protocol
when such is required to be submitted to the Agency for review.
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3. Failure to submit on the required schedule an adequate progress report on a study
as required by this Notice.
4. Failure to submit on the required schedule acceptable data as required by this
Notice.
5. Failure to take a required action or submit adequate information pertaining to any
option chosen to address the data requirements (e.g., any required action or
information pertaining to submission or citation of existing studies or offers,
arrangements, or arbitration on the sharing of costs or the formation of Task
Forces, failure to comply with the terms of an agreement or arbitration concerning
joint data development or failure to comply with any terms of a data waiver).
6. Failure to submit supportable certifications as to the conditions of submitted
studies, as required by Section ni-C of this Notice.
7. Withdrawal of an offer to share in the cost of developing required data.
8. Failure of the registrant to whom you have tendered an offer to share in the cost of
developing data and provided proof of the registrant's receipt of such offer or
failure of a registrant on whom you rely for a generic data exemption either to:
a. inform EPA of intent to develop and submit the data required by this Notice
on a Data Call-In Response Form and a Requirements Status and
Registrant's Response Form;
b. fulfill the commitment to develop and submit the data as required by this
Notice; or
c. otherwise take appropriate steps to meet the requirements stated in this
Notice, unless you commit to submit and do submit the required data in the
specified time frame.
9. Failure to take any required or appropriate steps, not mentioned above, at any time
following the issuance of this Notice.
IV-B. BASIS FOR DETERMINATION THAT SUBMITTED STUDY IS
UNACCEPTABLE ~
The Agency may determine that a study (even if submitted within the required time) is
unacceptable and constitutes a basis for issuance of a Notice of Intent to Suspend. The grounds
for suspension include, but are not limited to, failure to meet any of the following:
1. EPA requirements specified in the Data Call-In Notice or other documents incorporated
by reference (including, as applicable, EPA Pesticide Assessment Guidelines, Data
Reporting Guidelines, and GeneTox Health Effects Test Guidelines) regarding the design,
conduct, and reporting of required studies. Such requirements include, but are not limited
54
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to, those relating to test material, test procedures, selection of species, number of animals,
sex and distribution of animals, dose and effect levels to be tested or attained, duration of
test, and, as applicable, Good Laboratory Practices.
2. EPA requirements regarding the submission of protocols, including the incorporation
of any changes required by the Agency following review.
3. EPA requirements regarding the reporting of data, including the manner of reporting,
the completeness of results, and the adequacy of any required supporting (or raw) data,
including, but not limited to, requirements referenced or included in this Notice or
contained in PR 86-5. All studies must be submitted in the form of a final report; a
preliminary report will not be considered to fulfill the submission requirement.
IV-C EXISTING STOCKS OF SUSPENDED OR CANCELLED PRODUCTS
EPA has statutory authority to permit continued sale, distribution and use of existing
stocks of a pesticide product which has been suspended or cancelled if doing so would be
consistent with the purposes of the Act.
The Agency has determined that such disposition by registrants of existing stocks for a
suspended registration when a section 3(c)(2)(B) data request is outstanding would generally not
be consistent with the Act's purposes. Accordingly, the Agency anticipates granting registrants
permission to sell, distribute, or use existing stocks of suspended product(s) only in exceptional
circumstances. If you believe such disposition of existing stocks of your product(s) which ma> he
suspended for failure to comply with this Notice should be permitted, you have the burden of
clearly demonstrating to EPA that granting such permission would be consistent with the Act You
must also explain why an "existing stocks" provision is necessary, including a statement of the
quantity of existing stocks and your estimate of the time required for their sale, distribution, and
use. Unless you meet this burden the Agency will not consider any request pertaining to the
continued sale, distribution, or use of your existing stocks after suspension.
If you request a voluntary cancellation of your product(s) as a response to this Notice and
your product is in full compliance with all Agency requirements, you will have, under most
circumstances, one year from the date your 90 day response to this Notice is due, to sell,
distribute, or use existing stocks. Normally, the Agency will allow persons other than the
registrant such as independent distributors, retailers and end users to sell, distribute or use such
existing stocks until the stocks are exhausted. Any sale, distribution or use of stocks of
voluntarily cancelled products containing an active ingredient for which the Agency has particular
risk concerns will be determined on case-by-case basis.
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Requests for voluntary cancellation received after the 90 day response period required by
this Notice will not result in the Agency granting any additional time to sell, distribute, or use
existing stocks beyond a year from the date the 90 day response was due unless you demonstrate
to the Agency that you are in full compliance with all Agency requirements, including the
requirements of this Notice; For example, if you decide to voluntarily cancel your registration six
months before a 3 year study is scheduled to be submitted, all progress reports and other
information necessary to establish that you have been conducting the study in an acceptable and
good faith manner must have been submitted to the Agency, before EPA will consider granting an
existing stocks provision.
SECTION V. REGISTRANTS' OBLIGATION TO REPORT POSSIBLE
UNREASONABLE ADVERSE EFFECTS
Registrants are reminded that FIFRA section 6(a)(2) states that if at any time after a
pesticide is registered a registrant has additional factual information regarding unreasonable
adverse effects on the environment by the pesticide, the registrant shall submit the information to
the Agency. Registrants must notify the Agency of any factual information they have, from
whatever source, including but not limited to interim or preliminary results of studies, regarding
unreasonable adverse effects on man or the environment. This requirement continues as long as
the products are registered by the Agency.
SECTION VI. INQUIRIES AND RESPONSES TO THIS NOTICE
If you have any questions regarding the requirements and procedures established by this
Notice, call the contact person(s) listed in Attachment 1, the Data Call-in Chemical Status Sheet.
All responses to this Notice (other than voluntary cancellation requests and generic data
exemption claims) must include a completed Data Call-In Response Form and a completed
Requirements Status and Registrant's Response Form (Attachment 2 and Attachment 3 for product
specific data) and any other documents required by this Notice, and should be submitted to the
contact person(s) identified in Attachment 1. If the voluntary cancellation or generic data
exemption option is chosen, only the Data Call-in Response Form need be submitted.
The Office of Compliance Monitoring (OCM) of the Office of Pesticides and Toxic
Substances (OPTS), EPA, will be monitoring the data being generated in response to this Notice.
Sincerely yours,
Lois A. Rossi, Director
Special Review and
Reregistration Division
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Attachments
1 - Data Call-In Chemical Status Sheet
2 - Product-Specific Data Call-In Response Form
3 - EPA Batching of End-Use Products for Meeting Acute Toxicology Data
Requirements for Reregistration
4 - List of Registrants Receiving This Notice
5 - Cost Share and Data Compensation Forms and the Confidential Statement of
Formula Form
57
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58
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CHLOEHEXIDINE DIACETATE DATA CALL-IN CHEMICAL STATUS SHEET
INTRODUCTION
You have been sent this Product Specific Data Call-In Notice because you have product(s)
containing Chloehexidine diacetate.
This Product Specific Data Call-In Chemical Status Sheet, contains an overview of data
required by this notice, and point of contact for inquiries pertaining to the reregistration of
Chloehexidine diacetate. This attachment is to be used in conjunction with (1) the Product Specific
Data Call-In Notice, (2) the Product Specific Data Call-In Response Form (Attachment 2), (3) the
Requirements Status and Registrant's Form (Attachment 3), (4) EPA's Grouping of End-Use
Products for Meeting Acute Toxicology Data Requirement (Attachment 4), (5) the EPA Acceptance
Criteria (Attachment 5), (6) a list of registrants receiving this DCI (Attachment 6) and (7) the Cost
Share and Data Compensation Forms in replying to this Chloehexidine diacetate Product Specific
Data Call-In (Attachment 7). Instructions and guidance accompany each form.
DATA REQUIRED BY THIS NOTICE
The additional data requirements needed to complete the database for Chloehexidine diacetate
are contained in the Requirements Status and Registrant's Response, Attachment 3. The Agency has
concluded that additional data on Chloehexidine diacetate are needed for specific products. These
data are required to be submitted to the Agency within the time frame listed. These data are needed
to fully complete the reregistration of all eligible Chloehexidine diacetate products.
INQUIRIES AND RESPONSES TO THIS NOTICE
If you have any questions regarding this product specific data requirements and procedures
established by this Notice, please contact C.P. Moran at (703) 308-8590.
All responses to this Notice for the Product Specific data requirements should be submitted
to:
C.P. Moran
Chemical Review Manager Team 81
Product Reregistration Branch
Special Review and Reregistration Branch 7508W
Office of Pesticide Programs
U.S. Environmental Protection Agency
. Washington, D.C. 20460
RE: Chloehexidine diacetate
59
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09
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INSTRUCTIONS FOR COMPLETING THE DATA CALL-IN RESPONSE FORM FOR
PRODUCT SPECIFIC DATA
Item 1-4. Already completed by EPA.
Item 5. If you wish to voluntarily cancel your product, answer "yes." If you choose this
option, you will not have to provide the data required by the Data Call-In Notice and
you will not have to complete any other forms. Further sale and distribution of your
product after the effective date of cancellation must be in accordance with the Existing
Stocks provision of the Data Call-In Notice (Section IV-C).
Item 6. Not applicable since this form calls in product specific data only. However, if your
product is identical to another product and you qualify for a data exemption, you
must respond with "yes" to Item 7a (MUP) or 7B (EUP) on this form, provide the
EPA registration numbers of your source(s); you would not complete the
"Requirements Status and Registrant's Response" form. Examples of such products
include repackaged products and Special Local Needs (Section 24c) products which
are identical to federally registered products.
Item 7a. For each manufacturing use product (MUP) for which you wish to maintain
registration, you must agree to satisfy the data requirements by responding "yes."
Item 7b. For each end use product (EUP) for which you wish to maintain registration, you
must agree to satisfy the data requirements by responding "yes." If you are
requesting a data waiver, answer "yes" here; in addition, on the "Requirements
Status and Registrant's Response" form under Item 9, you must respond with Option
7 (Waiver Request) for each study for which you are requesting a waiver. See Item
6 with regard to identical products and data exemptions.
Items 8-11. Self-explanatory.
You may provide additional information that does not fit on this form in a signed
letter that accompanies this form. For example, you may wish to report that your
product has already been transferred to another company or that you have already
voluntarily canceled this product. For these cases, please supply all relevant details
so that EPA can ensure that its records are correct.
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DRAFT COPY
United States Environmental Protection Agency
Washington, D. C. 20460
DATA CALL-IN RESPONSE
ink-Please read carefuny the attached
this form.
Page 1 of
••^—^-^^_
Form Approved
OMB No. 2070-0107
2070-0057
Approval Expires 03-31-96
1. Company name and Address
SAMPLE COMPANY
NO STREET ADDRESS
NO CITY, XX 00000
4. EPA Product
Registration
NNNNNN-NNNNN
5. I wish to
cancel this
product regis-
tration volun-
tarily.
2. Case tt and Name
3038 Chlorhexidine derivs.
6. Generic Data
Data Exemption because I
obtain the active ingredient
from the source EPA regis-
tration number listed below.
N.A.
6b. I agree to satisfy Generic
Data requirements as indicated
on the attached form entitled
"Requirements Status and
Registrant's Response."
N.A.
8. Certification
I certify that the statements made on this form and all attachments are true, accurate, and complete
I acknowledge that any knowingly false or misleading statement may be punishable by fine, imprisonment
or both under applicable law.
ignature and Title of Company's Authorized Representative
3. Date and Type of DCI
PRODUCT SPECIFIC
7. Product Specific Data
7a. My product is a MUP and
I agree to satisfy the MUP
requirements on the attached
form entitled "Requirements
Status and Registrant's
Response."
10. Name of Company Contact
7b. My product is an EUP am
I agree to satisfy the EUP
requirements on the attached
form entitled "Requirements
Status and Registrant's
Response."
9. Date
11. Phone Number
-------
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INSTRUCTIONS FOR COMPLETING THE REQUIREMENTS STATUS AND
REGISTRANT'S RESPONSE FORM FOR PRODUCT SPECIFIC DATA
Item 1-3 Completed by EPA. Note the unique identifier number assigned by EPA in Item
3. This number must be used in the transmittal document for any data
submissions in response to this Data Call-In Notice.
Item 4. The guideline reference numbers of studies required to support the product's
continued registration are identified. These guidelines, in addition to the requirements
specified in the Notice, govern the conduct of the required studies. Note that series
61 and 62 in product chemistry are now listed under 40 CFR 158 155 through
158.180, SubpartC.
Item 5. The study title associated with the guideline reference number is identified.
Item 6. The use pattern(s) of the pesticide associated with the product specific requirements
is (are) identified. For most product specific data requirements, all use patterns are
covered by the data requirements. In the case of efficacy data, the required studies
only pertain to products which have the use sites and/or pests indicated.
Item 7. The substance to be tested is identified by EPA. For product specific data, the
product as formulated for sale and distribution is the test substance except in'rare
cases.
Item 8. The due date for submission of each study is identified. It is normally based on 8
months after issuance of the Reregistration Eligibility Document unless EPA
determines that a longer time period is necessary.
Item 9. Enter only one of the following response codes for each data requirement to show
how you intend to comply with the data requirements listed in this,table. Fuller
descriptions of each option are contained in the Data Call-In Notice.
1. I will generate and submit data by the specified due date (Developing Data). By
indicating that I have chosen this option, I certify that I will comply with all the
requirements pertaining to the conditions for submittal of this study as outlined in the
Data Call-In Notice. By the specified due date, I will also submit: (1) a completed
"Certification With Respect To Data Compensation Requirements" form (EPA
Form 8570-29) and (2) two completed and signed copies of the Confidential
Statement of Formula (EPA Form 8570-4).
2. I have entered into an agreement with one or more registrants to develop data jointly
(Cost Sharing). I am submitting a copy of this agreement. I understand that this
option is available only for acute toxicity or certain efficacy data and only if EPA
indicates in an attachment to this Notice that my product is similar enough to another
product to qualify for this option. I certify that another party in the agreement is
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committing to submit or provide the required data; if the required study is not
submitted on time, my product may be subject to suspension. By the specified due
date, I will also submit: (1) a completed "Certification With Respect To Data
Compensation Requirements" form (EPA Form 8570-29) and (2) two completed
and signed copies of the Confidential Statement of Formula (EPA Form 8570-4).
3. I have made offers to share in the cost to develop data (Offers to Cost Share). I
understand that this option is available only for acute toxicity or certain efficacy data
and only if EPA indicates in an attachment to this Data Call-In Notice that my product
is similar enough to another product to qualify for this option. I am submitting
evidence that I have made an offer to another registrant (who has an obligation to
submit data) to share in the cost of that data. I am also submitting a completed
"Certification of Offer to Cost Share in the Development Data" form. I am
including a copy of my offer and proof of the other registrant's receipt of that offer.
I am identifying the party which is committing to submit or provide the required data;
if the required study is not submitted on time, my product may be subject to
suspension. I understand that other terms under Option 3 in the Data Call-In Notice
(Section m-C.l.) apply as well. By the specified due date, I will also submit: (1) a
completed "Certification With Respect To Data Compensation Requirements"
form (EPA Form 8570-29) and (2) two completed and signed copies of the
Confidential Statement of Formula (EPA Form 8570-4).
4. By the specified due date, I will submit an existing study that has not been submitted
previously to the Agency by anyone (Submitting an Existing Study). I certify that
this study will meet all the requirements for submittal of existing data outlined in
Option 4 in the Data Call-In Notice (Section m-C.l.) and will meet the attached
acceptance criteria (for acute toxicity and product chemistry data). I will attach the
needed supporting information along with this response. I also certify that I have
determined that this study will fill the data requirement for which I have indicated this
choice. By the specified due date, I will also submit a completed "Certification With
Respect To Data Compensation Requirements" form (EPA Form 8570-29) to
show what data compensation option I have chosen. By the specified due date, I will
also submit: (1) a completed "Certification With Respect To Data Compensation
Requirements" form (EPA Form 8570-29) and (2) two completed and signed copies
of the Confidential Statement of Formula (EPA Form 8570-4).
5. By the specified due date, I will submit or cite data to upgrade a study classified by
the Agency as partially acceptable and upgradable (Upgrading a Study). I will
submit evidence of the Agency's review indicating that the study may be upgraded
and what information is required to do so. I will provide the MRID or Accession
number of the study at the due date. I understand that the conditions for this option
outlined Option 5 in the Data Call-In Notice (Section m-C.l.) apply. By the
specified due date, I will also submit: (1) a completed "Certification With Respect
To Data Compensation Requirements" form (EPA Form 8570-29) and (2) two
65
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completed and signed copies of the Confidential Statement of Formula (EPA Form
*
6. By the specified due date, I will cite an existing study that the Agency has classified
as acceptable or an existing study that has been submitted but not reviewed by the
Agency (Citing an Existing Study). If I am citing another registrant's study, I
understand that this option is available only for acute toxicity or certain efficacy data
and only if the cited study was conducted on my product, an identical product or a
product which EPA has "grouped" with one or more other products for purposes of
depending on the same data. I may also choose this option if I am citing my own
data. In either case, I will provide the MRTO or Accession number(s) for the cited
data on a "Product Specific Data Report" form or in a similar format. By the
specified due date, I will also submit: (1) a completed "Certification With Respect
To Data Compensation Requirements" form (EPA Form 8570-29) and (2) two
completed and signed copies of the Confidential Statement of Formula (EPA Form
8570-4) .
7. I request a waiver for this study because it is inappropriate for my product (Waiver
Request). I am attaching a complete justification for this request, including technical
reasons, data and references to relevant EPA regulations, guidelines or policies
[Note: any supplemental data must be submitted in the format required by P.R. Notice
86-5]. I understand that this is my only opportunity to state the reasons or provide
information in support of my request. If the Agency approves my waiver request, I
will not be required to supply the data pursuant to Section 3(c)(2)(B) of FIFRA. 'if
the Agency denies my waiver request, I must choose a method of meeting the data
requirements of this Notice by the due date stated by this Notice. In this case, I must,
within 30 days of my receipt of the Agency's written decision, submit a revised
Requirements Status and Registrant's Response" Form indicating the option chosen
I also understand that the deadline for submission of data as specified by the original
data call-in notice will not change. By the specified due date, I will also submit- (1)
a completed "Certification With Respect To Data Compensation Requirements"
form (EPA Form 8570-29) and (2) two completed and signed copies of the
Confidential Statement of Formula (EPA Form 8570-4).
Items 10-13. Self-explanatory.
NOTE: You may provide additional information that does not fit on this form in a signed
letter that accompanies this form. For example, you may wish to report that your
product has already been transferred to another company or that you have already
voluntarily canceled this product. For these cases, please supply all relevant details
so that EPA can ensure that its records are correct.
66
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DRAFT COPY
United States Environmental Protection Agency
Washington, D. C. 20460
REQUIREMENTS STATUS AND REGISTRANT'S RESPONSE
INSIKUCTIONS: Please type or print in ink. Please read carefully
Use additional sheet (s) if necessary.
1 . Company name and Address
SAMPLE COMPANY
NO STREET ADDRESS
NO CITY, XX 00000
4. Guideline
Requirement
Number
61-1
61-2 (a)
61-2 (b)
62-1
62-2
62-3
63-2
63-3
63-4
63-7
63-12
63-13
the attached instructions and supply the information requested
2 . Case ft and Name
3038 Chlorhexidine derivs .
EPA Reg. No. NNNNNN-NNNNN
5. Study Title
Prod diem - Reqular Chemical
Product identity & composition (1)
Descriptn starting materials, (1,2)
productn & formulatn
process
Discussion of formation of (1,3)
impurities
Preliminary analysis (1,4)
Certification of limits (1,5)
Analytical method (1)
Color (i7)
Physical state
Odor (17)
Density
PH (9)
Study not required for product
R
0
T
O
C
0
L
Progress
Reports
1
2
3
6. Use
Pattern
ABCDEFGHIJKLMNO
ABCDEFGH I JKLMNO
ABCDEFGHIJKLMNO
ABCDEFGHIJKLMNO
ABCDEFGHIJKLMNO
ABCDEFGHIJKLMNO
ABCDEFGHIJKLMNO
ABCDEFGHIJKLMNO
ABCDEFGHIJKLMNO
ABCDEFGHIJKLMNO
ABCDEFGHIJKLMNO
Form Approved
2070-0057
Approval Expires 03-31-96
on this form.
3. Date and Type of DCI
PRODUCT SPECIFIC
ID# NNNNNN-RD-NNNN
7. Test
Substance
MP/EP
MP/EP
MP/EP
MP/EP
MP/EP
MP/EP
MP/EP
MP/EP
MP/EP
MP/EP
MP/EP
I certify that the statements made on this form and all attachments are true, accurate and eomnloi-..
I acknowledge that any knowingly false or misleading statement may
or both under applicable law.
Signature and Title of Company's Authorized Representative
be punishable by fine, imprisonment
32. Name of Company Contact ~ —
8 . Time
Frame
8 mos .
8 mos .
8 mos .
8 mos .
8 mos.
8 mos .
8 mos .
8 mos .
8 mos .
8 mos.
8 mos .
8 mos .
9. Registrant
Response
11. Date
1 3 . Phone Number
67
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DRAFT COPY
Pacrp 9 of t
United States Environmental Protection Agency
Washington, D. C. 20460
REQUIREMENTS STATUS AND REGISTRANT'S RESPONSE
INSTRUCTIONS: Please type or print in ink. Please read carefully
Use additional sheet (s) if necessary.
1 . Company name and Address
SAMPLE COMPANY
NO STREET ADDRESS
NO CITY, XX 00000
4. Guideline
Requirement
Number
63-14
63-15
63-16
63-17
63-18
63-19
63-20
63-21
81-1
81-2
81-3
81-4
81-5
81-6
the attached instructions and supply the information requested
2. Case H and Name
3038 Chlorhexidine derivs .
EPA Reg. No. NNNNNN-NNNNN
5. Study Title
specific reregistration.
Oxidizing or reducing action (10)
Flammability (H)
Explodability (12)
Storage stability (is)
Viscosity (13)
Miscibility (14)
Corrosion characteristics
Dielectric breakdown voltage (IS)
Acute Toxic - Regular Chemical
Acute oral toxicity-rat (1,36,37)
Acute dermal (1,2,37)
toxicity- rabbit /rat
Acute inhalation toxicity-rat (3)
Primary eye irritation-rabbit (2)
Primary dermal irritation (1,2)
Dermal sensitization (4)
p
R
0
T
0
C
0
L
Progress
Reports
1
2
3
6. Use
Pattern
ABCDEFGHI JKLMNO
ABCDEFGHI JKLMNO
ABCDEFGHI JKLMNO
ABCDEFGHI JKLMNO
AB CDE FGH I JKLMNO
ABCDEFGHI JKLMNO
ABCDEFGHI JKLMNO
ABCDEFGHI JKLMNO
ABCDEFGHI JKLMNO
ABCDEFGHI JKLMNO
ABCDEFGHI JKLMNO
ABCDEFGHI JKLMNO
ABCDEFGHI JKLMNO
ABCDEFGHI JKLMNO
Initial to ii rli a! f <. »i t i I ir-*t i"n «.« to infoi-mat |r>n nn 'hi* f*i» ' '
'f'jll '•••,' •'• .,,.,fj ,. , ,„ ,, ,, p,,,. „„.,
7. Test
Substance
Form Approved
OMB No. 2070-0107
2070-0057
Approval Expires 03-31-96
on this form.
3. Date and Type of DCI
PRODUCT SPECIFIC
ID# NNNNNN-RD-NNNN
MP/EP
MP/EP
MP/EP
MP/EP
MP/EP
MP/EP
MP/EP
MP/EP
MP/EP
MP/EP
MP/EP
MP/EP
MP/EP
MP/EP
8 . Time
Frame
8 mos .
8 mos.
8 mos .
8 mos .
8 mos .
8 mos .
8 mos .
8 mos.
8 mos.
8 mos .
8 mos .
8 mos.
8 mos .
8 mos.
9. Registrant
Response
Date
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DRAFT COPY
Page 3 of 3
United States Environmental Protection Agency
Washington, D. C. 20460
REQUIREMENTS STATUS AND REGISTRANT'S RESPONSE
INSTRUCTIONS: Please type or print in ink. Please read carefully
Use additional sheet (s) if necessary.
1 . Company name and Address
SAMPLE COMPANY
NO STREET ADDRESS
NO CITY, XX 00000
4. Guideline
Requirement
Number
91-2, 7
91-2, 7
the attached instructions and supply the information requested
2 . Case ft and Name
3038 Chlorhexidine derivs .
EPA Reg. No. NNNNNN-NNNNN
5. Study Title
Efficacy - Antimicrobial Aqents - Public
Health Daea
Miscellaneous Indoor Hard
Surfaces
AOAC use-dilution method (1,2)
Virucidal activity study (1,2)
roooHosot
Progress
Reports
1
2
3
6. Use
Pattern
Initial to indicate certification as to information on this page
(full tfxt of certification i n on paqp one!
LMNO
LMNO
Form Approved
OMB No. 2070-0107
2070-0057
Approval Expires 03-31-96
on this form.
3 . Date and Type of DCI
PRODUCT SPECIFIC
ID# NNNNNN-RD-NNNN
7. Test
Substance
EP
EP
8 . Time
Frame
8 mos .
8 mos .
9. Registrant
Response
Date
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DRAFTCOPY
Page 1 of 2
United States Environmental Protection Agency
Washington, D. C. 20460
FOOTNOTES AND KEY DEFINITIONS FOR GUIDELINE REQUIREMENTS
Case # and Name: 3038 Chlorhexidine derivs.
inr
TEP - typical — pr°™< - techni -< — --ngr^^^
Use Categories Key:
~ ™
FOOtnOteS: [The following notes are referenced in column two (5. Study Title, of the REQUIREMENTS STATUS AND REGISTRANT'S RESPONSE form
Prod Chem - Regular Chemical
2 „_ .. __. . . .
full scale production and an experimental
the extenrthis6!^^^^!^6!^^!^^11 ^^ Pr°dUCtl°n a"d *" exPeriraental use permit is sought, a discussion of unintentional ingredients shall be submitted to
4 To support registration of an MP or EP whether croduced hv an i nt-erti-at-oH = „!- •_
3 ux r,t-, wnetner proaucea Dy an integrated system or not, the technical qrade of Active
grade of Active Ingredient cannot be isolated, a statement of composition of the practical e ivalr— -« *°- !--*,?
Data on EPs or MPs will be required on a case-by-case basis
5 Certified limits are not required for inert ingredients in products proposed for experimental use
9 Required if test subst.ances are dispersible with water.
10 Required if product contains an oxidizing or reducing agent.
11 Required if product contains combustible liquids.
12 Required if product is potentially explosive.
13 Required if product is a liquid.
14 Required if product is an emulsifiable liquid and is to be diluted with petroleum solvents
15 Required if end-use product is liquid and is to be used around electrical equipment.
17 Not required unless efficacy data are required.
of instability are reported. Refer to PR Notice 92-5 for more information * °^aaates are detected, or ,c, product instability is suspected or inci
Acute Toxic - Regular Chemical
1 Not required if test material is a gas or highly volatile
2 Not required if test material is corrosive to s.in or has'pH less than 2 or greater than n.S; such a product will be classified as Toxicity Category ! on the basis
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—— Page 2 of
United States Environmental Protection Agency
Washington, D. C. 20460
FOOTNOTES AND KEY DEFINITIONS FOR GUIDELINE REQUIREMENTS
Case # and Name: 3038 Chlorhexidine derivs.
Footnotes (cont.):
of potential eye and dermal irritation effects.
Retired unless receatedT"8! ' "*' " "?" C°nditi°nS °f USe "iU result in' a" inhala"e material ,e. g.. gas. volatile substances, or aerosol/particulate, .
Required unless repeated dermal exposure does not occur under conditions of use
navrdeLstrated T^^'l T*"? ^f"10' i8 ^^ f°r org.nopho.p.tes. and may be required for other cholinesterase inhibitors and other pesticides
'""ion of studies "^ '"^ ^ ViS"al SyStem' Ita'1«""t' Sh°uld ^ ^ «^h th. agency for development of protocols and methodology
" restriction'to usV^c'T I" T^" "° ^ "." "' '' ^^ " " "" ^ reasonab^ Anticipated that the results of such testing may meet the criteria for
restriction to use by certified applicators specified in 40 CFR 152.170(b) or the criteria for initiation of special review specified in 40 CFR 154.7 (a) (1).
Efficacy - Antimicrobial Agent
1 Efficacy data for antimicrobial agents that claim to control pest microorganisms that may pose a threat to human must be submitted
'
forrsk/benf
for risk/benefit analyses such as for public interest findings and cases of special review
tO be Developed and maintained in the registrant's file and must be submitted to the Agency on a case-by-caae basis
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EPA'S BATCHING OF CHLORHEXIDINE PRODUCTS FOR MEETING ACUTE
TOXICITY DATA REQUIREMENTS FOR REREGISTRATION
In an effort to reduce the time, resources and number of animals needed to fulfill the
acute loxicily data requirements for reregistration of products containing chlorhexidine as the
active ingredient, the Agency has batched products which can be considered similar for purposes
of acute toxicity. Factors considered in the sorting process include each product's active and inert
ingredients (identity, percent composition and biological activity), type of formulation (e.g.,
emulsifiable concentrate, aerosol, wettable powder, granular, etc.), and labeling (e.g., signal
word, use classification, precautionary labeling, etc.). Note that the Agency is not describing
batched products as "substantially similar" since some products within a batch may not be
considered chemically similar or have identical use patterns.
Using available information, batching has been accomplished by the process described in
the preceding paragraph. Notwithstanding the batching process, the Agency reserves the right to
require, at any time, acute toxicity data for an individual product should the need arise.
Registrants of products within a batch may choose to cooperatively generate, submit or
cite a single battery of six acute lexicological studies to represent all the products within that
batch. It is the registrants' option to participate in the process with all other registrants, only
some of the other registrants, or only their own products within a batch, or to generate all the
required acute lexicological studies for each of their own products. If a registranl chooses lo
generate ihe dala for a baich, he/she musi use one of ihe producls wilhin ihe balch as ihe tesi
material. If a regisiranl chooses lo rely upon previously submitted acute loxicily data, he/she
may do so provided that the data base is complete and valid by today's standards (see acceptance
criteria attached), the formulation tested is considered by EPA to be similar for acute toxicity,
and the formulation has noi been significantly altered since submission and acceptance of the '
acute toxicity data. Regardless of whether new data is generated or existing data is referenced,
registrant must clearly identify the test material by EPA Registration Number. If more than one
confidential statement of formula (CSF) exists for a product, the registrant must indicate the
formulation actually tested by identifying the corresponding CSF.
In deciding how to meet the product specific data requirements, registrant must follow
the directions given in ihe Dala Call-In Notice and ils attachment appended lo Ihe RED. The
DCI Notice conlains Iwo response forms which are lo be completed and submitted lo ihe Agency
wilhin 90 days of receipt The firsl form, "Dala Call-In Response," asks whelher ihe regisiranl
will meel ihe dala requirement for each producl. The second form, "Requiremenls Slalus and
Regisiranl's Response," lisls ihe producl specific dala required for each producl, including ihe
slandard six acute loxicily tests. A registranl who wishes lo participate in a balch musl decide
whelher he/she will provide ihe dala or depend on someone else lo do so. If a regisiranl supplies
Ihe dala lo support a balch of producls, he/she musl selecl one of ihe following options:
Developing Dala (Option 1), Submitting an Existing Sludy (Option 4), Upgrading an Existing
Sludy (Option 5) or Citing an Existing Sludy (Option 6). If a regisiranl depends on anolher's
dala, he/she musl choose among: Cosl Sharing (Option 2), Offers lo Cosl Share (Option 3) or
72
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Citing an Existing Study (Option 6). If a registrant does not want to participate in a batch, the
choices are Options 1, 4, 5 or 6. However, a registrant should know that choosing not to
participate in a batch does not preclude other registrants in the batch from citing his/her studies
and offering to cost share (Option 3) those studies.
Two products were found which contain chlorhexidine as an active ingredient, 1117-30
and 1117-48. The products have not been placed into a batch. However, data generated on
1117-48 may be used to support both products.
Table 1
Batch
1
EPA Reg. No,
13808-7
35975-4
35978-8
39508-2
46779-1
56228-22
% Active Ingredient
1.0
1.0
1.0
1.0
1.0
1.0
Formulation Type
Liquid
Liquid
Liquid
Liquid
Liquid
Liquid
The following table lists a product that was either considered not to be similar or the
Agency lacked sufficient information for decision making and were not placed in any batch. The
registrant of this product is responsible for meeting the acute toxicity data requirements
separately.
Table 2 (No Batch)
EPA Reg. No.
56228-26
% Active Ingredient
90.0
Formulation Type
Solid
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— Page 1 of
United States Environmental Protection Agency
Washington, D. C. 20460
LIST OF ALL REGISTRANTS SENT THIS DATA CALL-IN NOTICE
Case # and Name: 3038 Chlorhexidine derivs.
Co. Nr. Company Name Additional Name Address City & State
Zip
001117 FORT DODGE LABORATORIES HQME pRQDS CQRp ^ ^ poRT ^^ ^
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75
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Instructions for Completing the Confidential Statement of Formula
The Confidential Statement of Formula (CSF) Form 8570-4 must be used. Two legible,
signed copies of the form are required. Following are basic instructions:
a. All the blocks on the form must be filled in and answered completely.
b. If any block is not applicable, mark it N/A.
c. The CSF must be signed, dated and the telephone number of the responsible
party must be provided.
d. All applicable information which is on the product specific data submission
must also be reported on the CSF.
e. All weights reported under item 7 must be in pounds per gallon for liquids and
pounds per cubic feet for solids.
f Flashpoint must be in degrees Fahrenheit and flame extension in inches.
g. For all active ingredients, the EPA Registration Numbers for the currently
registered source products must be reported under column 12.
h. The Chemical Abstracts Service (CAS) Numbers for all actives and inerts and
all common names for the trade names must be reported.
i. For the active ingredients, the percent purity of the source products must be
reported under column 10 and must be exactly the same as on the source
product's label.
j. All the weights in columns 13.a. and 13.b. must be in pounds, kilograms, or
grams. In no case will volumes be accepted. Do not mix English and metric
system units (i.e., pounds and kilograms).
k. All the items under column 13.b. must total 100 percent.
1 All items under columns 14.a. and 14.b. for the active ingredients must
represent pure active form.
m. The upper and lower certified limits for ail active and inert ingredients must
follow the 40 CFR 158.175 instructions. An explanation must be provided if
the proposed limits are different than standard certified limits.
n. When new CSFs are submitted and approved, all previously submitted CSFs
become obsolete for that specific formulation.
76
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77
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78
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-J
VO
\7C
EPA USi
TM Confidential Statement of Formula
ONLY
1 6. Typed
18. Signa
into the formulation Give common^ accepted chemical
name, trade nama. ami CAS number.!
LJ Alternate Formulation
see instructions on Back
2. Name and Address of Producer (Include ZIP Coda)
4. Registration No./File Symbol
7. Pounds/Gal or Bulk Density
11. Supplier Nama & Address
ure of Approving Official
5 EPA Product Mgr/Tiam No
8. pH
12. EPARog No.
13. Each Component
in Formulation
a. Amount t. % by Wt^h
1 7. Total Weight
19. Title
100%
6. Country Where Formulated
9. Flash Point/Flame Extension
U C«n.(.»d Limns
% by Weight
1 5 Purpos* in
formulation
20 Phone No (Include Area Codel
21 Date
EPA Form 8570-4 (Rev. 12-90) Previous edition, .re obsolete. If you can photocopy this, please submit an additional copy. White - EPA File Copy (original) Yellow - Applicant copy
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o
00
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?/EPA
United States Environmental Protection Agency
Washington, DC 20460
CERTIFICATION OF OFFER TO COST
SHARE IN THE DEVELOPMENT OF DATA
Form Approved
OMB No. 2070-01QB
2070-0057
Approval Expire* 3-31-%
Public reporting burden for this collection of informalfon is estimated to average 15 minutes per response, including
time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and
completing and reviewing the collection of information. Send comments regarding the burden estimate or any other
aspect of this collection of information, Including suggestions for reducing this burden, to Chief. Information Policy
Branch, PM-223, U.S. Environmental Protection Agency. 401 M St., S.W.. Washington. DC 20460; and to the Office
of Management and Budget, Paperwork Reduction Project (2070-0106). Washington. DC 20503.
Please fill In blanks below.
Compun} Mime
Company Number
EPA Reg. No.
I Certify that:
My company is willing to develop and submit the data required by EPA under the authority of the Federal
Insecticide. Fungicide and Rodenticide Act (FIFRA), if necessary. However, my company would prefer to
enter into an agreement with one or more registrants to develop jointly or share in the cost of developing
data.
My firm has offered in writing to enter into such an agreement. That offer was irrevocable and included an
offer to be bound by arbitration decision under section 3(c)(2)(B)(iii) of FIFRA if final agreement on all
terms could not be reached otherwise. This offer was made to the following firm(s) on the following
date(s):
Nam* of Flrm(i)
Date of Offer
Certification:
I certify that I am duly authorized to represent the company named above, and that the statements that I have made on
this form and all attachments therein are true, accurate, and complete. I acknowledge that any knowingly false or
misleading statement may be punishable by fine or imprisonment or both under applicable law.
I Signature of Company's Authorized Representative
Nam* and Title (Pleaae Type or Print)
Dale
F.PA Form 8570-32 (5/91) Replaces EPA Komi 8580, which is obsolete
81
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82
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United States Environmental Protection Agency
Washington, DC 20460
CERTIFICATION WITH RESPECT TO
DATA COMPENSATION REQUIREMENTS
Form Approved
OMB No. 2070-0107,
2070-0057
Approval Expires
3-31-96
3 reporting burden for this collection of information is estimated to average 15 minutes per response, including time for
ving instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing the
;tion of information. Send comments regarding the burden estimate or any other aspect of this collection of information,
ling suggestions for reducing this burden to, Chief Information Policy Branch, PM-233, U.S. Environmental Protection
cy, 401 M St., S.W., Washington, DC 20460; and to the Office of Management and Budget, Paperwork Reduction Project
1-0106), Washington, DC 20503.
se fill in blanks below.
tny Name
:tName
Company Number
EPA Reg. No
ifythat:
:or each study cited in support of registration or reregistratiion under the Federal Insecticide, Fungicide and Rodenteid* Ac*
A) that is an exclusive use study, I am the original data submitter, or I have obtained the written permission of the or.g.n*
submitter to cite that study.
'hat for each study cited in support of registration or reregistration under FIFRA that is NOT an exclusive use study ' •• «•
al data submitter, or I have obtained the written permission of the original data submitter, or I have notified in writing f»
any(ies) that submitted data I have cited arid have offered to: (a) Pay compensation for those data in accordance wt*
)(F) and 3(c)(2)(D) of FIFRA; and (b) Commence negotiation to determine which data are subject to the compensator
ement of FIFRA and the amount of compensation due, if any. The companies I have notified are. (check one)
he companies who have submitted the studies listed on the back of this form or attached sheets, or indicated on the •-
irements Status and Registrants' Response Form,"
hat I have previously complied with section 3(c)(1)(F) of FIFRA for the studies I have cited in support of registration 0'
stration under FIFRA.
ire
Date
ind Tide (Please Type or Print)
iRAL OFFER TO PAY: I hereby offer and agree to pay compensation to other persons, with regard to the registration o»
stration of my products, to the extent required by FIFRA section 3(c)(1)(F) and 3(c)(2)(D).
re
Date
/id Title (Please Type or Print)
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The following is a list of available documents for Chlorhexidine diacetate that my further
assist you in responding to this Reregistration Eligibility Decision document. These
documents may be obtained by the following methods:
Electronic
File format: Portable Document Format (.PDF) Requires Adobe® Acrobat or compatible
reader. Electronic copies can be downloaded from the Pesticide Special
Review and Reregistration Information System at 703-308-7224. They also are
available on the Internet on EPA's gopher server, GOPHER.EPA.GOV or
using ftp on FTP.EPA.GOV, or using WWW (World Wide Web) on
WWW.EPA.GOV., or contact C.P. Moran at (703)-308-8590.
1. PR Notice 86-5.
2. PR Notice 91-2 (pertains to the Label Ingredient Statement).
3. A full copy of this RED document.
4. A copy of the fact sheet for Chlorhexidine diacetate.
The following documents are part of the Administrative Record for Chlorhexidine
diacetate and may included in the EPA's Office of Pesticide Programs Public Docket Copies
of these documents are not available electronically, but may be obtained by contacting the
person listed on the Chemical Status Sheet.
1. Health and Environmental Effects Science Chapters.
2. Detailed Label Usage Information System (LUIS) Report.
The following Agency reference documents are not available electronically, but may be
obtained by contacting the person listed on the Chemical Status Sheet of this RED document.
1. The Label Review Manual.
2. EPA Acceptance Criteria
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