&EPA
United States
Environmental Protection
Agency
Prevention, Pesticides
And Toxic Substances
(7508W)
EPA738-R-95-034
October 1995
Reregistration
Eligibility Decision (RED)
***BRONOPOL
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United States
Environmental Protection
Agency
Prevention, Pesticides
And Toxic Substances
(7508W)
:EPA-738-F-95-Oi9
October 1995^
FACTS
Pesticide
Re registration
Bronopol
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 reregistration, 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 reregistration, 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
reregistration case 2770, bronopol.
Bronopol is used as a microbiocide/microbipstat in oil field systems,
air washer systems, air conditioimig/humidifying systems, cooling water
systems, papermills, absorbent clays, metal working fluids, printing inks,,
paints, adhesives and consumer/institutional products. A formulating
technical material is also registered.
A pesticide product containing bronopol as an active ingredient was
first registered hi the United States hi 1984 for use in industrial bactericides,
slimicides and preservatives.
In 1987, EPA issued the Antimicrobial Data Call-In Notice to obtain
chronic and subchronic toxicity data for bronopol and other antimicrobials.
A Data Call-In was issued for this chemical as part of the reregistration
program in June 1991, and a second Data Call-In, for confirmatory
exposure data, was issued in September 1995.
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Human Health
Assessment
Toxicity
In laboratory animal studies measuring acute toxicity, technical grade
brpnopol has been shown to cause severe effects by the dermal route,
placing it in Toxicity Category I (the highest of four categories) for dermal
toxicity. It has been shown to produce irritation in eye and dermal irritation
studies, placing it in Toxicity Category I for eye irritation and Toxicity.
Category n for skin irritation. It is moderately toxic in oral toxicjty studies,
placing it in Toxicity Category n for oral toxicity. In an acute inhalation
study, bronopol was found to be slightly toxic, placing it hi Toxicity
Category IV. This chemical is not a skin sensitizer based on a study using
guinea pigs.
A 90-day oral toxicity study using rats indicated that bronopol is a
severe gastrointestinal irritant. A similar study in beagle dogs indicated only
treatment related effects of increased liver and spleen weights hi the high
dose group.
In a 90-day dermal toxicity study hi rabbits, the NOEL for systemic
toxicity was 2 mg/kg/day. >
A chronic feeding/carcinogenicity study with rats resulted in high
mortality, stomach lesions, and severe reduction in body weight gain. From
a chronic dermal/carchiogenicity study, mice exhibited, moderate reduction
hi body weight gain. The Office of Pesticide Programs Reference Dose
(RfD)/Peer Review Committee evaluated the carcinogenic potential of
bronopol on April 18, 1995. The Committee classified bronopol as a Group
E chemical ( one for which there is evidence of noncarcinogenicity for
humans), based on a lack of evidence of cancer effects in acceptable studies
with two animal species, the rat and mouse.
Developmental toxicity studies were conducted using rats and rabbits.
The results showed marginal to no effects hi the rat study and effects only at
the high dose level hi the rabbit study.
A reproductive toxicity study using rats resulted hi effects at the mid
to high dose levels. The results included increases in kidney, thyroid and
adrenal weights, decreases hi liver weights, and decreased body weights.
Bronopol was not mutagenic hi four mutagenicity studies. Metabolism
studies indicate that bronopol is primarily excreted in the urine.
Dietary Exposure
No dietary exposure is expected from the pesticide uses of bronopol
since no food or feed uses are registered. However, an RfD was established
recently at 0.1 mg/kg/day because the data base is available and because of
possible long-term exposure to bronopol-containing products.
Occupational and Residential Exposure
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Environmental
Assessment
Based on current use patterns, the potential exists for exposure and
risks to handlers using open pour application methods for liquid
formulations in water cooling systems. The margin of exposure (MQE) for
the above liquid formulation application method is 14 which is unacceptable
to the Agency. However, the MOE for the same liquid formulation
application method using a metered systems is acceptable at 1,596. The
Agency also believes formaldehyde may be released when bronopol
decomposes in. aqueous solutions.
Human Risk Assessment
Since bronopol has no food or feed uses, dietary risk is not .expected.
Bronopol is severely acutely toxic by the dermal route and is a corrosive eye
irritant (Toxicity Category I). Based on unacceptable MOE for handlers
using open pour application methods of liquid formulations to water cooling
systems, the Agency is requiring metered pump systems for all water
cooling system uses.
EPA is requiring that labels contain a statement advising workers to
wear personal protective equipment(PPE), consisting of a long sleeved shirt
and long pants, socks plus shoes, and chemical resistant gloves. Chemical
resistant gloves are required for application of the end-use product to protect
applicators'skin.
Although bronopol may release formaldehyde in aqueous solutions,
minimal risk is expected due to the chemical's slow decomposition, and
because OSHA has a standard to monitor workers' exposure to
formaldehyde during industrial uses of bronopol in occupational settings.
No additional human health risk of concern is expected.
Environmental Fate
The Agency does not anticipate ground water contamination from the
uses of bronopol. Although bronopol has high water solubility, high
solubility in polar solvents, low solubility in nonpolar solvents, and
fevorable partitioning into water, the Agency feels that bronopol's short-
lived environmental persistence reduces the potential for groundwater
contamination. . • . - •" . - -.
Bronopol is stable to hydrolysis under normal conditions. However,
at wanner temperatures and/or higher pH's, rapid hydrolysis may occur.
Under these conditions, hydrolysis products include formaldehyde and lesser
amounts of other degradates. Judging from its low octanol/water ratio and
high solubility in water, bronopol is not expected to bioaccumulate. In
tested mammalian species metabolism is reported to be rapid and complete,
and accumulation does not occur.
Ecological Effects
Bronopol is practically nontoxic to slightly toxic to birds; slightly to
moderately toxic to freshwater fish and terrestrial invertebrates; moderately
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to highly toxic to estuarine/marine invertebrates; and slightly toxic to
estuarine/marine fish.
Ecological Effects Risk Assessment
Risk to nontarget aquatic organisms can be expected through point
source discharge of industrial microbiocides. In the case of bronopol, there
are several use sites and environmental conditions where exposure to aquatic
organisms is a possibility. However, industrial effluent discharges are
governed by NPDES permits granted by state regulatory agencies and EPA.
EPA is requiring product-specific data, including product chemistry
and efficacy <&**» revised Confidential Statements of Formula (CSFs), and
revised product labeling for reregistration of products containing bronopol.
Additional Data
Required
Product Labeling The labels of all registered pesticide products containing bronopol
Changes must comply with EPA' s current pesticide labeling requirements. In
Required addition:
Requirements: ,
All end-use (and manufacturing-use) products that may be contained in
an effluent discharged to the waters of the U.S. or municipal sewer systems
must be used in accordance with the requirements of the National Pollutant
Discharge Elimination System (NPDES) permitting program.
. ____ , ' ., . , , )
Application Restrictions -The labels of all end-use products
containing bronopol must bear the following restrictions:
"Do not apply by open-pouring of liquid to cooling water systems; a
metering pump delivery system is required for this use and application
, method."
Registrants must specify on labeling the complete directions for use
for each use pattern: site of application, type of application, timing of
application, equipment used for application, and the rate of application
(dosage).
To clarify the intent of the oil recovery drilling muds/packer fluids use
(as an aquatic or terrestrial non-food use pattern), the following statement
must be added to the labels for terrestrial non-food oil/gas drilling muds and
packer fluids:
"For use in terrestrial wells only." .
And the following statement must be added to the precautionary labeling:
"Do not apply in marine and/or estuarine oil fields."
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The following statement must be added to the labels for aquatic non-food
industrial drilling muds and packer fluids:
"For use in off-shore wells only.."
For use in both terrestrial and offshore drilling muds and packer fluids:
\ ... ^- , • . , . • •
"This product may be used in terrestrial and off-shore oil drilling muds and
packer fluids."
Handler PPE for Occupational-Use Products - The personal
protective equipment (PPE) for handlers engaged in occupational uses is
long sleeve shirt and long pants, socks plus shoes, as well as chemical-
resistant gloves.
"Do not apply this product in a way that will contact workers or other
persons." ( '
" Discard clothing or other absorbent materials that have been drenched or
heavily contaminated with this product's concentrate. Do not reuse them."
"Follow manufacturer's instructions for cleaning/maintaining PPE. If there
are no such instructions for washables, use detergent and hot water. Keep
and wash PPE separately from other laundry."
Recommendations:
The labels of all bronopol end-use products must contain the following
statements: > ,
"Users should wash hands before eating, drinking, chewing gum, using
tobacco, or using the toilet."
- ' ' . \ • - '. ,
"Users should remove, clothing immediately if pesticide gets inside. Then
wash thoroughly.and put on clean clothing."
"Users should remove PPE immediately after handling this product. Wash
the outside of gloves before removing. As soon as possible, wash
thoroughly and change into clean'clothing." ,
Regulatory ~ The uses of currently registered bronopol products with the above
Conclusion limitations, will not pose unreasonable risks to humans or the environment.
Therefore, all uses of these products are eligible for reregistration.
These bronopol products will be reregistered once the required
product-specific data, revised Confidential Statements of Formula, and .
• •' . ' .r. • ' '• '' • ' '..,''- . . •
evised labeling are received and accepted by EPA.
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For More
Information
EPA is requesting public comments on the Reregistration Eligibility
Decision (RED) document for bronppol 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 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 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.
Printed copies of the RED and feet 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, fex 513-489-8695.
Following the comment period, the bronopol 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 bronopol RED, or reregistration of individual products containing
bronopol, 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 8:00 am and 6:00-pm Central Time, Monday
through Friday.
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
OFFICE OF .
PREVENTION, PESTICIDES
AND TOXIC SUBSTANCES
CERTEPIPn MATT.
MAY 22'1996
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/active ingredient
bronopol. The enclosed Reregistratinn PJifihility 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 date of this letter. The second set of required responses are due 8 months from the
date of this letter. .Complete and timely responses will avoid the Agency taking the
enforcement action of suspension against your products. '
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 Mr.
, Frank Rubis (703) 308-8184. Address any questions on generic data to the Special Review
and Reregistotion Division representative Mr. Ron Kendall (703) 308-8068.
, 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)
DATA CALL-IN (PCI) OR "90-DAY RESPQNSE"-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 date of this letter (RED issuance date);
otherwise, your product may be suspended.
TIME EXTENSIONS AND DATA WAIVER REQUESTS-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. . "•'..-. -
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 #PB?2-221811; 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 (MRTD) numbers: Before citing these studies, you must
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make sure that they meet the Agency's acceptance criteria (attached to the
DCI).
>> :
d, Two copies of the Confidential Statement of Formula (CSF) for each basic
and each alternate formulation. The labeling and CSF which you submit for
each product must comply with P.R. 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 §158475) 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 Requirements. Complete
and sign EPA form 8570-31 for each product.
COMMENTS IN RESPONSE TO FEDERAL REGISTER NOTICE-Comments
pertaining to the content of the RED may be submitted to the address shown hi the
Federal Register Notice which announces the availability of this RED.
WHERE TO SEND PRODUCT SPECIFIC DCI RESPONSES (90-DAY) AND
APPLICATIONS FOR REREGISTRAT1ON (8-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 reregistration determination within 14
months after the RED has been issued.
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REREGISTRATION ELIGIBILITY DECISION
BRONQPOL
LISTB
CASE2770
ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF PESTICIDE PROGRAMS
SPECIAL REVIEW AND REREGISTRATION DIVISION
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TABLE OF CONTENTS
BRONOPOL REREGISTRATION ELIGIBILITY DECISION TEAM . . ........ i
E3&CUTIVE SUMMARY . . . ... .'.\ . . . ' . . . .... . . .... . . . .'.'. .... . v
i -i
I. INTRODUCTION ; . ...... ., . . . ; . ..;.,.: ... .'. . . . 1
H. CASE OVERVIEW . . . ...... ... . . . . . ... . . . ... . . ... . . ... 2
A. Chemical Overview 2
B. UseProfile .....................,...;.........,...... 2
,C. Regulatory History .......' .... 5
HI. SCIENCE ASSESSMENT .:.,..;.......... . , . . '. ......... .5
A. Physical Chemistry Assessment . . .... . . . . . . . . . . . . ... .5
B. Human Health Assessment . . 6
- 1. Toxicology Assessment ............ . . ................ 6
a. Acute Toxicity . . ...... . . . . . . . . .... 6
. . , b. Subchronic Toxiciify . ......................... .'8
c. Chronic Toxicity and Carcinogenicity .............. 9
d. Developmental Toxicity ... ;......,.... . 12
e. Reproductive Toxicity . ... . ... ........ . . . .... . . 14
f. Mutagenicity .............................. 15
g. Metabolism . ..................... . ......... 16
h. Reference Dose .........;.... 17
, i. Toxicological Endpoints of Concern ...'-..'... '. .'. .... 17
2. Exposure and Risk Assessment . . . .... . . .,. . . . . . . ... . . .18
a. Dietary Exposure and Risk Assessment 18
b. Occupational Handler Exposure Assessment 18
c. Occupational Handler Risk Assessments . . . .21
d. Occupational Post-Application Exposure and Risk ..... 22
e. Residential Exposure and Risk ... . .... . . . . . . . . . .,. 22
f. Formaldehyde Exposure and Risk .......... . .... . 23
C. Environmental Assessment. . . ..... . . . . .... . . . ... .... . . . . . 23
1. Ecological Toxicity Data . . . . . .", . . . ... ......... . . ... 23
a. Toxicity to Terrestrial Animals ,,.........,. 23
b. Toxicity to Aquatic Animals 24
2. Environmental Fate . .................;. ... . 26
a. Environmental Fate Assessment .................. 26
b. Environmental Fate and Transport 27
3. Environmental Exposure and Risk ...................... 28
IV. RISKMANAGEMENT AND REREGISTRATION DECISION'... ......... 28
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A. Determination of Eligibility . ' ,..:.. 28
B. Determination of Eligibility Decision 29
1. Eligibility Decision . ........ . ......... 29
2. Eligible and Ineligible Uses 29
C. Regulatory Position . . . . 30
1. Occupational Risk Mitigation Measures/Labeling Rationale .... 30
2. Aquatic Risk Mitigation/Labeling Rationale 30
3. Other Labeling Requirements 31
V. ACTIONS REQUIRED OF REGISTRANTS . . '. 31
A. Manufacturing-Use Products . . 31
1. Additional Generic Data Requirements .-.••.• 31
B. End-Use Products 32
1. Additional Product-Specific Data Requirements 32
2. Labeling Requirements for End-Use Products ............. 32
3. Existing Stocks • • • • • 35
VI. APPENDICES '. .-.' •...':.' 37
APPENDIX A. Table of Use Patterns Subject to Registration . .-.. .... 38
APPENDIX B. Table of the Generic Data Requirements and Studies Used to
Make the Reregistration Decision 64
APPENDIX C. Citations Considered to be Part of the Data Base Supporting the
Reregistration of bronopol .68
APPENDIX D. Product Specific Data Call-In .75
Attachment 1. Chemical Status Sheets . 88
Attachment 2. Product Specific Data Call-In Response Forms (Form A
inserts) Plus Instructions 90
Attachment 3. Product Specific Requirement Status and Registrant's
Response Forms (Form B inserts) and Instructions 94
Attachment 4. EPA Batching of End-Use Products for Meeting Data
Requirements for Reregistration 101
Attachment 5. List of All Registrants Sent This Data Call-in (insert)
Notice ........... f ...".,.. ...'. 104
Attachment 6. Cost Share, Data Compensation Forms, Confidential
Statement of Formula Form and Instructions ....-.'. 105
APPENDIX E. List of Available Related Documents Ill
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BRONOPOL REREGISTRATION ELIGIBILITY DECISION TEAM
Office of Pesticide Programs: . '
Biological and Economic Analysis Division
Kathleen, Vinlove
Michelle Cottril
Phyllis Johnson
Environmental Fate and Effects Division
Linda Kutney
Mary Powell
Alex Clem
Health Effects Division
Tom Myers
Krystyna Locke
Winston Dang
Registration Division
Valdis Goncarovs
Bipin Gandhi
Mark Perry
Special Review and Reregistration Division
Kathleen Depukat
Ron Kendall
Office of Compliance:
Rick Colbert >
Economic Analysis Branch
Biological Analysis Branch
Biological Analysis Branch
Science Analysis and Coordination Staff
Science Analysis and Coordination Staff
Environmental Fate and Groundwater Branch
Risk Characterization Analysis Branch
Toxicology Branch I
Occupational and Residential Exposure Branch
Antimicrobial Program Branch
Registration Support Branch
Registration Support Branch
Accelerated Reregistration Branch
Accelerated Reregistration Branch
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11
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ADI
AE
a.i.
ARC
CAS
CI
CNS
CSF
DFR
ORES
DWEL
EEC
EP -
EPA
FDA
FIFRA
FFDCA
FOB
GLC
GM
GRAS
HA
HOT
LC50
LD
50
lo
LD,
LEL
LOG
LOD
LOEL
MATC .
MCLG
ug/g
mg/L
MOE
MP
MPI
MRID
N/A ,
NOEC
NPD'ES
GLOSSARY OF TERMS AND ABBREVIATIONS
Acceptable Daily Intake. A now defunct term for reference dose (RfD).
Acid Equivalent
Active Ingredient i ,
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/l,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. '
Microgfams 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
National Pollutant Discharge Elimination System .
Ill
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GLOSSARY OF TERMS AND ABBREVIATIONS
NOEL No Observed Effect Level " . ,
NOAEL No Observed Adverse Effect Level
OP Organophosphate
OPP * Office of Pesticide Programs .
PADI Provisional Acceptable Daily Intake • '
PAG Pesticide Assessment Guideline
PAM Pesticide Analytical Method '
PHED Pesticide Handler's Exposure Data
ppb Parts Per Billion
PPE Personal Protective Equipment
ppm Parts Per Million
PRN Pesticide Registration Notice
Q*, The Carcinogenic Potential of a Compound, Quantified by the EP A's Cancer Risk Model
RBC . Red Blood Cell
RED Reregistration Eligibility Decision
REI -. Restricted Entry Interval
RfD Reference Dose
RS Registration Standard
SLN Special Local Need (Registrations Under Section 24 (c) of FIFRA)
TC ' Toxic Concentration. The concentration at which a substance produces a toxic effect.
TD Toxic Dose. The dose at which a substance produces a toxic effect.
TEP Typical End-Use Product
TGAI Technical Grade Active Ingredient
TLC Thin Layer Chromatography , .
TMRC Theoretical Maximum Residue Contribution
torr A unit of pressure needed to support a column of mercury 1 mm high under standard conditions.
FAO/WHQ Food and Agriculture Organization/World Health Organization
WP Wettable Powder
WPS Worker Protection Standard
IV
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EXECUTIVE SUMMARY
Reregistration Eligibility and Background
The U.S. Environmental Protection Agency (referred to as "the Agency") has completed
an assessment of the potential human health and environmental risks associated with the pesticide
uses of 2-bromo-2-nitropropane-l,3-diol, hereafter referred to as "bronopol." The Agency has
determined that pesticide products containing this chemical as an active ingredient, labeled and
used as specified in. this Reregistration Eligibility Decision document (RED),', will not cause
unreasonable risk to humans or the environment. This document is requiring the use of closed
metering systems for liquid applications to cooling water systems and the use of personal
protective equipment to mitigate risks to handlers. Therefore, the Agency has concluded that the
products containing bronopol for all currently registered uses are eligible for reregistration.
Use Patterns
Bronopol products are currently registered for use in oil-field systems, air washer systems,
industrial processing water and scrubbing systems, laboratory equipment water baths, coatings,
emulsions, ah- conditioning/humidifying systems, cooling water systems, pulp and papermill water
systems, components used in papermakmg, metal working cutting fluids, printing inks, paints,
and adhesives as well as consumer/institutional products. A formulating technical material is also
registered.
Health Effects and Occupational Exposure
Studies suggest that bronopol is a-corrosive eye irritant and a moderate to severe dermal
irritant in rabbits. However, the Agency does not categorize bronopol as a dermal sensitizer. The
short and intermediate-term occupational/residential risks for bronopol are based on the maternal
and developmental toxicity NOEL of 40 mg/kg/day. The NOEL of 10 mg/kg/day from a chronic
rat feeding study is used to estimate risk. A reference dose (RfD) was established because of
possible long-term exposure to bronopol containing products. The Agency has concluded there
is an unacceptable risk to handlers from open pouring of liquid bronopol products into cooling
water systems. The use of a closed metering system will mitigate this risk. Risks from Other
exposures are within acceptable limits.
Environmental Fate and Ecological Effects
Bronopol is moderately to highly toxic to estuarine/marine invertebrates; slightly toxic to
estuarine/marine fish; slightly toxic to birds on a acute oral basis; and practically nontoxic to
slightly toxic to birds on a subacute dietary basis. However, a quantitative risk assessment has
not been conducted. For bronopol, risk to the aquatic environment is addressed under the NPDES
permitting program by the EPA, Office of Water. The Agency currently requires that labels for
all bronopol products require that discharges to aquatic environments comply with an NPDES
permit.
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Product Reregistration
Before reregistering the products containing bronopol, 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 EOFRA, the Agency will reregister
a product. Those products which contain other active ingredients will be eligible for
reregistration only when the other active ingredients are determined to 'be eligible for
reregistration. ,
VI
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I.
INTRODUCTION
In 1988, the Federal Insecticide, Fungicide, and Rodehticide Act (FIFRA) was amended
to accelerate the reregistration of products with active ingredients registered prior to November
1, 1984. The amended Act provides a schedule for the reregistration process to be completed in
nhie years. There are five phases to the reregistration process. The first four phases of the process
focus on identification of data requirements to support the reregistration 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 att data submitted
to support reregistration.
FIFRA Section 4(g)(2)(A) states that in Phase 5 "the Administrator shall determine
whether pesticides containing such active ingredient are eligible for reregistration" before calling
in data on products and either reregistering products or taking "other appropriate regulatory
action." Thus, reregistration 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 ihe 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 reregistration eligibility of
the registered uses of bronopol. The document consists of six sections. Section I is the
introduction. Section n describes bronopol, its uses, data requirements and regulatory history.
Section in discusses the human health and environmental assessment based on the data available
to the Agency. Section IV presents the reregistration decision for bronopol. Section V discusses
the reregistration requirements for bronopol. 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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CASE OVERVIEW
A. Chemical Overview
The following active ingredient is covered by this Reregistration Eligibility
Decision: .
Common Name:
Chemical Name:
CAS Registry Number:
OPP Chemical Code:
Empirical Formula:
Bronopol
2-Bromo-2-riitropropane-l ,3-diol
52-51-7
216400
C3H6BrN04
Trade and Other Names: Onyxide 500
Basic Manufacturer:
The Boots Company, Nottingham, England
John W. Kennedy Consultants
(U.S. Agent)
B. Use Profile
The following is information on the currently registered uses for bronopol with an
overview of use sites and application methods. A detailed table of the uses of bronopol
is in Appendix A.
TYPE OF PESTICIDE:
USE SITES:
Microbiocide/Microbiostat (Slime-Forming Bacteria, Fungi,
and Algae); may be used in formulating disinfectants and
sanitizers, as well as microbiocides.
Aquatic Non-Food Industrial
Ah- Conditioner/Refrigeration Condensate Water Systems
Air Washer Water Systems
Commercial/Industrial Water Cooling Systems
Evaporative Condenser Water Systems
Heat Exchanger Water Systems
Humidifier Water (commercial/industrial humidifying systems)
Industrial Processing Water J
Industrial Scrubbing System
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Laboratory Equipment Water Baths
*OU Recovery Drilling Muds/Packer Fluids (off-shore sites)
Pulp/Paper Mill Water Systems
Secondary Oil Recovery Injection Water
Indoor Non-Food
Adhesives, Industrial .
Coatings, Industrial •.
Emulsions, Resin/Latex/Polymer
Fuels/Oil Storage Tank Bottom Water Additive
MeMworking Cutting Fluids
Paints, Latex (In-Can)
Paper/Paper Products
Pasteurizer/Wanner/Cannery Cooling Water Systems
Specialty Industrial Products
Wet-End Additives/Industrial Processing Chemicals
Terrestrial Non-Food Crop
*Oil Recovery Drilling Muds/Packer Fluids (terrestrial sites)
*Registrants must specify on labels, as per Section V of this document, whether the
product is used on off-shore and/or terrestrial sites.
PESTS: Slime-forming bacteria, fungi, and algae; sulfate-reducing bacteria; aerobic
and anaerobic bacteria; odor-causing bacteria; spoilage bacteria.
FORMULATION TYPES REGISTERED:
TYPE: End-Use, Manufacturing-Use. •
FORM: Pelleted/Tableted, Crystalline, Soluble Concentrate/Liquid, Soluble
Concentrate/Solid. ' ;
METHODS AND RATES OF APPLICATION:
TYPES.OF TREATMENT: Water treatment, Water treatment (recirculating system),
V Impregnation treatment (absorbent clays), Industrial
preservative treatment, Preservative treatment. ,
EQUIPMENT:
Metering Pump, Sprayer, Injection Equipment, Not
specified on label (registrant needs to specify on labeling).
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TIMING: Continuous feed (initial), Continuous feed (subsequent),
Intermittent (slug)(initialj, Intermittent (slug)(subsequent),
Intermittent feed (initial), Shock/slug, During manufacture,
Initial, Subsequent/maintenance, Not specified (registrant
needs to specify on labeling).
RATE OF APPLICATION (Microbiocide/Microbiostat):
Adhesives: 34-5156 ppm active ingredient. '.
Emulsions: 11-498 ppm active ingredient.
Latex paints: 82-498 ppm active ingredient. ,
Absorbent clay: 20-200 ppm active ingredient.
Consumer, household, and institutional products; water-based agricultural
pesticide concentrates; raw materials; surfactants; water-based printing inks
and fount solutions: 2-498 ppm active ingredient.
Polymers, defoamers, dyes, alum, starch, pigment slurries, extender slurries,
coating components, titanium dioxide, calcium carbonate, and clay slurries for
use in paper-making systems: 2-498 ppm active ingredient.
Metalworking cutting fluids: For metalworking cutting fluids concentrates, the
amount to be incorporated during manufacture will depend on the dilution factor
recommended for the concentration; for diluted metalworking cutting fluids: 82-
1000 ppm active ingredient.
Oil recovery drilling muds/packer fluids: 21-200 ppm active ingredient.
Bottom water in oil or transportation tanks, pipeline maintenance: 10-200
ppm active ingredient.
Humidifier water (commercial/industrial systems): 24-100 ppm active
ingredient. '
t ' ' '
Air conditioner/refrigeration condensate and ah* washer water systems: 24-
100 ppm active ingredient.
Commercial/industrial water cooling systems/evaporative condenser,
pulp/paper mill, and heat exchanger water systems: 8.6-264 ppm active
ingredient.
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Pasteurizer/warmer/cannery cooling water systems: 17-57 ppm active
ingredient.
Industrial processing water: 8-102 ppm active ingredient.
Industrial scrubbing system: 17-57.ppm active ingredient. :
Secondary oil recovery injection water: 24-488 ppm active ingredient.
Laboratory equipment water baths: 101 ppm active ingredient.
Paper products: No dosage specified on label. Registrant must specify dosage
on labeling.
USE PRACTICES LIMITATIQNS:
Do not discharge effluent containing brqnoppl into sewage systems without
notifying the sewage treatment plant authority. Do not discharge effluent containing
brbnopol into lakes, streams, ponds, estuaries, oceans, or public water (NPDES license
restriction). Bronopol is not cleared for use in defoamers and/or coatings that may come
in contact with food.
C. Regulatory History
Pesticide products containing 2-bromo-2-nitropropane-l,3-diol (bronopol) as an
active ingredient were initially registered in the United States in 1984 for use in industrial
bactericides, sUmicides and preservatives.
There are currently 21 products registered that contain bronopol as the active
ingredient. A formulating technical material is also registered. Three Data Call-Ins were
issued by EPA for this chemical. The Antimicrobial Data Call-In was issued in March
1987. A second Data Call-in, was issued as part of the Phase 4 reregistration in June
1991. The Agency required additional exposure data or compensation for available data
to support the risk assessment for reregistration hi a third Data Call-in in October 1995.
HI. SCIENCE ASSESSMENT
A. Physical Chemistry Assessment
The chemical bronoppl is a propanediol-type compound containing nitro and
bromine groups. It is a white, crystalline powder with a faint odor and a melting point
of 130°C. Bronopol is soluble in polar solvents such as water, ethanol and ethylene glycol,
but only slightly soluble hi non-polar solvents like chloroform. It has a low vapor pressure
of 1.26 x 10~5 mm of Hg at 20°C. It is stable to room temperature, high temperature, and
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in sunlight. It decomposes in alkaline medium. An aqueous solution of bronopol degrades
in the presence of cupric and ferric ions as well as aluminum and tin metals. (MRIDs
108808, 141875, and 141876)
B. Human Health Assessment
1. Toxicology Assessment
The lexicological data base on bronopol is adequate and will support
reregistration eligibility.
a* Acute Toxicity
Acute toxicity studies with bronopol have been submitted and
adequately satisfy the Agency's requirements. Table 1 below summarizes
the values and categories for the various acute toxicology studies.
" ' ' "'TabieT Acute Toxicity* Values 1,**
STUDY
Acute Oral LD50- rat
Acute Dermal LD™- rabbit
Acute Inhalation LC^ - rat
(MKED 43530401)
Eye Irritation - rabbit*
Dermal Irritation - rabbit*
Dermal Sensitization - guinea pig*
RESULTS
males 307 mg/kg
females 342 mg/kg
64 -160 mg/kg
> 0.588 mg/L
corrosive
slight to severe
negative
*.r - ' w fc, &' r
CATEGORY
n
I
m
I
n
* This study is a requirement for manufacturing-use and end-use products (40 CFR 158). The bronopol
data have been generated on the TGAI and are presented here for informational purposes.
In an acute oral toxicity study with rats dosed with bronopol (ai
2^98.8%), clinical signs of sedation,.nasal exudate, gasping, wheezing,
cyanosis, and convulsions were noted. The acute oral LD50 was 307 mg/kg
for males and 342 mg/kg for females. Bronopol is moderately toxic by the
oral route. (MRID 00098396)
Results from an acute dermal toxicity study while inadequate,
suggest bronopol is highly toxic by the dermal route. Bronopol (ai
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_>98.8%) \vas administered to 2 male rats per dose at the dose levels of 0,
64, 160, 400 or 1000 mg/kg. Clinical signs noted were edema,
hemorrhage, labored breathing, prostration, and lung congestion. The
results of this study suggest that the acute dermal LD50 is 64 to 160 mg/kg.
(MRIDs 00098396 and 00138755) A new study is not required due to the
corrosive properties of bronopol.
Two acute inhalation studies suggest bronopol is slightly toxic to
practically non-toxic for this end point. For risk assessment purposes the
Agency has used the most conservative data and placed bronopol in toxicity
category HI for the inhalation route.
In one inhalation study, piloerection, hunched posture and
hydronephrosis were observed in male and female rats at the 0.089 mg/L
concentration of bronopol (ai ^98.8%). Clinical signs observed in the
0.588 mg/L group included diffuse red lungs, sore eyelids, and severe
dermatitis and ulceratipn on the head (attributed to dermal exposure).
Particle size was 1,3-6.7 /on. The Agency concludes from the results of
this study that bronopol is slightly toxic with an acute inhalation LC50 >
0.588 mg/L. (MRID 43530401)
In the second inhalation study, male rats were exposed to
concentrations of 0, 0.05, 0.5 or 5.0 mg/L of bronopol (ai >_98.S%).
Particle size was 1-5/t (50-81%) and 1-15/* (78-92%). Clinical signs noted
were eye irritation, dyspnea, profuse mucus production and lethargy during
exposure and chronic pneumonitis thereafter. The LC50 determined in this
study is > 5 mg/L.(MRIDO0098397)
In a primary eye. irritation study, bronopol (ai ^>98.8%) was
instilled as a 5% solution in polyethylene glycol 400 to rabbits. Strongly
irritating (redness and swelling of the conjunctiva, with moderate
discharge) effects were noted 1 hour after dosing and subsided in'all but
one rabbit by the 7th day after treatment. The results of this study
determined that bronopol is a corrosive eye irritant, placing it in toxicity
category I. (MRID 00160998)
In a primary dermal irritation study, bronopol (ai J>98.8%) was
tested at 0, 0.5, 2 or 5% in aqueous methylcellulose. Slight to moderate
erythema and slight to severe edema was noted on the intact skin of females
at 24 hours after termination of the 6-hour exposure. The results of this
, study determined that bronopol was a slight to severe irritant, placing it in
toxicity category n. (MRID 00098396)
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In a study to determine the dermal sensitization potential of
bronopol (ai J>98.8%), guinea pigs received dermal applications of 1 % in
acetone. Bronopol was determined hot to be a skin sensitizer after three
induction treatments on the outer surface of each ear and one week later,
one challenge treatment on the back and flank. A positive control response
was obtained with DCNB (dinitrochlorpbenzene). (MRIDs 00098398 and
00138755)
b. SubchronicToxicity '.
In an oral toxicity study, male and female SPF fats, 20/sex/group,
were administered bronopol (ai ^98.8%) daily by gavage for 13 weeks.
The dose levels used were 0, 20, 80 or 160 mg/kg/day. Due to high
mortality, dosing at the 160 mg/kg level was stopped after 8 days and
survivors were sacrificed on day 9. In the low-dose group, 1 female died
during week 10, 1 male had kidneys with distended tubules containing
eosinophUic material and another male had kidneys with dilated tubules
containing the eosinophUic material in the corticomedullary junction. In
the mid-dose group, 7 males (35%) and 9 females (45%) died, and gaseous
and fluid distention of the gastrointestinal (GI) tract was seen at autopsy.
Other toxic signs observed in the mid-dose group were respiratory distress
(gasping, wheezing) in the majority of rats, decreased body weight gain in
males (7-20%) throughout the study and in females (12-16%) during the
first 2 weeks of treatment when compared with the controls, and distended
or dilated tubules with eosinophUic material in the kidneys of one male.
In the high-dose group, males and females weighed 29% and 13%,
respectively, less than did the controls before they died during the first
week after dosing. Other toxic signs in the high-dose group included
severe respiratory distress and gaseous or fluid distention of the GI tract in
the majority or rats, and hemorrhagic foci hi and raised white areas on the
mucosa of the glandular stomach hi a few rats. Many rats exhibited GI
lesions (superficial ulceration with underlying inflammation, epithelial
hyperplasia and hyperkeratosis) and regressive changes in the thymus
marked by almost complete absence of lymphatic tissue. The macroscopic
and microscopic changes noted above indicate that bronopol is a severe GI
irritant. Based on the above findings, the NOEL and LOEL for systemic
toxicity, for both sexes, are 20 mg/kg/day and 80 mg/kg/day, respectively.
(MRTO 00098384) .
In an oral toxicity study with male and female beagle dogs,
3/sex/group were administered bronopol (ai >99.2%) daUy by gavage for
13 weeks. The dose levels used were 0, 4, 8 or 20 mg/kg/day and were
based on the results of a preliminary study in which 2 beagle dogs (male
and female) were dosed daUy at levels of 20-40 mg/kg for 2 weeks.
8
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Treatment-related effects, observed only in the high-dose group, were
increased liver (15%) and spleen (39%) weights, when organ weights were
expressed as percentages of body weights. Based on these findings, the
NOEL and LOEL for systemic toxicity, for both sexes, are 8 mg/kg/day
and 20 mg/kg/day, respectively' (MRID 00098399)
In a dermal toxicity study, male and female New Zealand white
rabbits, 5/sex/group, were exposed (abraded skin, dorsolumbar region) to
bronopol (ai jj>98%) for 3 weeks (6hours/day, 7 days/week). Bronopol
was suspended in 2.5% aqueous methyl cellulose solution at concentrations
of 0, 0.2% or 0.5% (w/v) and a dose volume of 1 mL/kg was applied to
an area of 10 cm2 (5% of total body surface). Treatment with the vehicle
(methyl cellulose) produced local skin irritation (slight to well defined
erythema) in all of the control rabbits. Similar reactions, although possibly
more persistent, were seen in rabbits treated with 0.2% bronopol.
Treatment with 0.5% bronopol caused stronger dermal reactions (moderate
erythema and edema, thickening, hardening and sloughing) and involved
extensive scabbing in the treated area. Neither test suspension induced any
other signs of toxicity or mortality. Based on dermal irritation, 0.2%
bronopol (2 mg/kg/day) is the NOEL and 0.5% bronopol (5 mg/kg/day)
is the LOEL. (MRTO 00098401) .
• * '- t -
c. Chronic Toxicity and Carcinogenicity •
In a chronic feeding/carcinogenicity study, Sprague-Dawley rats,
45/sex/dose in the main group and 15/sex/dose in the satellite group, were
administered bronopol (purity or a.i. content: J> 99.7%) hi acidified (pH
4) drinking water for 104 weeks. Based on the results of a preliminary •
study, the doses of bronopol selected for this study were 0, 10, 40 or 160
mg/kg/day (Groups 1, 2, 3 and 4, respectively). The actual intake of
bronopol (group mean values for weeks 0-104) was 0 • 10.5, 40.2 or 152.2
mg/kg/day for the males and 0, 10.4, 40.7 or 158.4 mg/kg/day for the
females. The satellite group was used for,the laboratory investigations
(hematdlogy, clinical chemistry and urinalysis).
Treatment-related effects were observed only in Groups 3 and 4.
However, the unpalatability of bronopol reduced the water intake, in a
dose-related manner, in all treated groups. Relative to the control values,
the statistically significant (P< 0.001) reduction in water intake in Group
2 (10 mg/kg/day) occurred mostly during the first 52 weeks and was 14-
25% for the male rats and 10-12% for the female rats.
In Group 3 (40 mg/kg/day), treatment-related effects included (a)
lower food intake (7%) during weeks 53-78 for the males; (b) reduced
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weight gain (20-52%, P<0.01 or 0.001) during weeks 27-78 for the
males; and (c) squamous metaplasia, inflammation or atrophic acini in the
salivary glands of 12/25 (48%) males and 3/23 (13%) females. Relative
to the control values, water consumption was reduced by 22-37%
(P<0.001) for the male rats during weeks 1-78 and by 15-24% (P<0.05,
0.01 or 0.001) for the female rats throughout the dosing period.
In Group 4 (160 mg/kg/day), treatment-related statistically
significant (P<0.01 and/or 0.001) effects included (a) reduced grooming
activity hi both sexes during the second year of dosing; (b) high mortality
in the males (80% hi each the main and the satellite groups) and the
females (62% hi the main group and 67% in the satellite group); (c)
decreased weight gain during weeks 3-78 among males (13-84%) and
during weeks 7-78 among females (11-53%); (d) weight loss during weeks
78-104 among males and females; (e) lower food intake among males (9-
16%) during weeks 13-104; (f) decreased absolute weights of heart (29%),
liver (35%), lungs (12%), seminal vesicles (47%), testes (20%) and thyroid
(26%), all hi males; (g) increased relative weights of adrenals, brain,
kidneys, liver and lungs in males and females; (h) increased relative
weights of pituitary hi males; (i) stomach lesions in 20/54 (37%) males and
15/52 (29%) females, whereas only 1/56 (1.8%) control males and 1/59
(1.7%) control females had these lesions; (j) increased incidence of
progressive glomerulonephrosis in males (48% vs 28% hi controls) and
females (38% vs 7.7% in controls); (k) sinusoid dilatation in the gastric '
lymph node hi 33% males and 23% females, whereas none was observed
hi the controls; and (1) squamous metaplasia, dilatation of the ducts, acinar
atrophy and/or hiflammation of the salivary glands in 12/13 (92%) males
and 11/20 (55%) females. Relative to the control Values, water
consumption was reduced by 32-53% for the male rats and by 24-40% for
the female rats throughout the dosing period. Because of a significant
decrease hi water consumption, the urine output was also reduced (10-46%
for males and 31-40% for females). Based on the above findings, the
systemic NOEL and LOEL for both sexes are 10 mg/kg/day and 40
mg/kg/day, respectively.
Bronopol was not carcinogenic in this study. The most frequently
observed tumors were pituitary adenoma in both sexes and mammary
fibroadenoma hi the females, but the incidence (number of rats with
tumor/number of rats examined) was dose-unrelated and was lowest hi the
high-dose group. The incidence of pituitary adenoma in the control, low-
dose, mid-dose and high-dose male rats was 10/43 (23%), 14/43 (32%),
7/42 (17%) and 2/41 (5%), respectively. The corresponding incidences in
the female rats were 20/44 (45%), 21/45 (47%), 23/42 (55%) and 14/38
(37%), respectively. The incidence of mammary fibroadenoma in the
10
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control, low-dosej mid-dose and high-dose female groups was 35/44
(79%), 36/45 (80%), 30/42 (71%) and 19/38 (50%), respectively.
(MRIDs 00098386, 00115645 and 00138766) \
/ In another carcinogenicity study, groups of CFLP mice of Swiss
origin, 52/sex/dpse, were administered bronopol dermally on Monday,
Wednesday and Friday of each week, for 80 weeks. The purity of bronopol
used was >^ 99.7%. Based on the results of a 4-week dermal preliminary
study, the concentrations (doses) of bronopol selected for .this study were
0, 0.2% and 0.5% as solutions in acetone (90%): water (10%), 0.3
mL/mouse/day. These doses were equivalent to 0, 0.6 and 1.5 mg of
bronopol/mouse/day, respectively, or (assuming the weight of a mouse to
be about 30 g) to 0, 20 mg/kg/day and 50 mg/kg/day, respectively.
Dermal exposure was used because, at that time, bronopol was intended for
use in topical preparations, as a preservative at a minimal concentration of
0.01 % and as an antibacterial agent at a maximal concentration of 0.5 %.
The only treatment-related effects observed were a minimal hair
loss in the high-dose (0.5%) males and females, and a decreased body
weight gain in the high-dose males. Hair loss was observed at the
periphery of the shaved area during the first 3 weeks of treatment among
"some mice" (numbers were not reported). Decreased body weight gain
occurred during weeks 26-80, but especially during weeks 26-52 when the
high-dose males gained 47% (P<0.01) less weight than did the controls.
Bronopol was-not carcinogenic in this study. Although only two
, dose levels were used, these appeared sufficient to evaluate the
carcinogenicity of bronopol by dermal route: The numbers of tumor-
bearing male mice hi the control, low-
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Non-neoplastic lesions were observed most frequently in the lungs
(lymphoid aggregations and/or alveoli with macrophages) ,and liver
(vacuolated, distended or degenerated hapatocytes) of male and female
mice, and in the ovaries (cysts), but were treatment-unrelated. (MRID
00098387)
The carcinogenic potential of bronopol was evaluated by the
Agency's Office of Pesticide Programs, Reference Dose (RfD)/Peer
Review Committee in 1995. The Committee classified bronopol as a
Group E carcinogen (evidence of noncarcinogenicity for humans), based
on a lack of evidence of carcinogenicity in acceptable studies with two
animal species, rat and mouse. The dose levels used in both studies were
considered to be adequate for carcinogenicity testing. This conclusion was
based on high mortality, stomach lesions and severe reduction in body
weight gain or weight loss in the rats, and on moderate reduction in body
weight gain in the mice and lack of statistically significant increases in
tumor frequencies between dose groups.
d. Developmental Toxicity
Bronopol (purity: 98%) was administered-by gavage in acidified
(pH 4) purified water to groups of 24 mated Sprague^Dawley rats at dose
levels of 0, 10, 28 or 80 mg/kg/day from gestation day (g.d.) 6 through 15
(g.d. 0 = detection of sperm hi vaginal lavage). Females were observed
for appearance of clinical signs and mortality, and body weight and food
consumption were determined at intervals during gestation. Animals were
sacrificed on g.d. 20 and reproductive observations were made. Uteri were
weighed and examined for live fetuses and intrauterine deaths. Fetuses
were weighed, sexed and examined for external, visceral and skeletal
alterations.
Marginal evidence of maternal toxicity was reported at the highest
dose tested and was evidenced by decreased body weight gain (80% less
than that for the control; P^O.Ol) during g.d.s 6-7, and slightly reduced
(1 %) body weight at day 7 when compared with the controls. No animals
were described in the report as having dose-related clinical signs. There
were no developmental effects that could be attributed to the administration
of bronopol. Based on these findings, the NOEL for maternal toxicity is
j>80 mg/kg/day (HDT) and the NOEL for developmental toxicity is also
> 80 mg/kg/day. The highest dose tested is considered adequate because
the results of a range-finding study indicated that doses ^100 mg/kg/day,
administered by gavage, caused severe gastrointestinal irritation mat led to
death. (MRTOs 43598701 and 43608501)
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In another developmental toxicology study, groups of 18, 19 or 20
mated female New Zealand White Rabbits received bronopol (purity:
99.8%) by gavage during g.d. 7 through 19 and were sacrificed on g.d. 28.
Aqueous solutions of bronopol, prepared just before use and acidified to
pH 4, were administered daily at the nominal dose levels of 0 (vehicle
control), 5, 20, 40 or 80 mg/kg/day and the dose volume of 2 mL/kg.
Separate solutions were prepared for each dose level and individual body
weights were obtained daily during the treatment period. The analytical
concentrations of bronopol in dosing solutions were very close to the
nominal concentrations (95-100%). The dose levels of bronopol used in
this study were selected by the sponsor after examination of data from a
range-finding study in mated rabbits (Report No. BON/2/91; not submitted
to the Agency for review).
The following maternal effects were observed only in the 80
mg/kg/day group: (a) body weight loss (0.06 kg, P< 0.001) during the
firsts days of treatment (g.d. 7-9); (b) decreased body weight gain during
g.d. 9-15 (13%); and (c) decreased food consumption during g.d.s 7-11
(38%, P< 0.001) and during g.d. 11-15 (19%).
The following developmental effects were observed only in the 80
mg/kg/day group: (a) decreased fetal body weight in both sexes (10%,
P<0.05); (b) increase in fetuses with major external/visceral and skeletal
abnormalities (6.9% vs 0% in the concurrent control group and 1.8% in
the historical controls); (c) increase in fetuses with minor skeletal
abnormalities (29.5%, P<0.01 vs. 10.2% in the concurrent control group;
and (d) an increased incidence of fetuses with skeletal variants (unossified
forelimb [8%] and hindlimb [16%] epiphyses). Based on these findings,
the NOEL and LOEL for maternal toxicity are 40 mg/kg/day and 80
mg/kg/day, respectively. The developmental NOEL and LOEL are also
40 mg/kg/day and 80 mg/kg/day, respectively. (MRTOs 42319601 and
42648201)
e. Reproductive Toxicity
' - ' -. •• ' • ' ' . - ' -
Charle,s River GOBS CD strain rats (13 males .and 26
females/group) were administered bronopol (purity: 99.9%) in drinking
(tap),water during the premating (80-87 days), mating, gestation and
lactation periods. The water was adjusted to a pH4 with hydrochloric acid
to ensure the stability of bronopol. The study involved parental group F0
and litters FIa and Flb, and parental group Fj and litters Fj, and F2b. The
Flb rats were used as the Fj parents. The target concentrations of bronopol
were 0, 0.025, 0.07 and 0.2%, corresponding to 0, 25, 70 and 200
mg/kg/day, respectively. The mean achieved doses of bronopol for the F0
13
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and Fj males and females were 0, 22.5, 55.2 and 147 mg/kg/day,
respectively. Dose concentrations were based on the results of a range-
finding study. (MRID 40660907)
Nothing remarkable was .observed in the low-dose (25 mg/kg/day
group. Systemic toxicity was observed mostly in the mid-dose (70
mg/kg/day) and high-dose (200 mg/kg/day) groups; in both generations.
Compared with the concurrent controls, toxic signs observed in the mid-
dose group included an increase in kidney weight of the F0 females (14.5 % •,
P < 0.01), decreased liver weight of the F, males (11 %) and females (11 %,
P<0.05, relative weight or organ/body weight ratio) and an increased
incidence of nephropathy in the F0 males (4/10 vs 2/10 in the controls) and
the F0 females (3/10 vs 0/10 in the controls).
Toxic signs noted in the high-dose group were (a) decreased body
weights of the F0 and/or F, females during the premating (7-24%, P < 0.05
or 0.01), gestation (5-16%) and/or lactation (8-11%) periods; (b) decreased
body weights of the F, males (11-22%, P<0.05 or 0.01); (c) decreased
food consumption of the F0 males (5-18%) and the F0 and Fj females (6-
16%); (d) increases in organ weights as follows: adrenals (22%, P<0.05,
F0 females), kidneys (36%, P<0.01, F0 females and 14%, P<0.05, F
males, both relative) and thyroid/parathyroid (26%, P<0.05, Fj males);
.(e) decreases in liver weight of the Fj males (21%, P<0.01); and (f) and
an increased incidence of nephropathy in the F0 males (6/10 vs 2/10 in the
controls) and females (9/10 vs 0/10 in the controls).
Reproductive toxicity was observed only in the high-dose group as
evidenced by a slight decrease in the female fertility index during the Fla.
mating (75% vs 87.5% in the controls).
Based on the above findings, the NOEL and LOEL for systemic
toxicity are 25 mg/kg/day and 70 mg/kg/day, respectively. The NOEL and
LOEL for reproductive toxicity are 70 mg/kg/day and 200 mg/kg/day,
respectively. (MRED 40660901 main study; MRID 41916502 - additional
data; and MRID 40660907 - range-finding study) t -
f. Mutagenicity
Bronopol was negative for mutagenicity in the Ames test using
Salmonella typhimurium strains TA1535, TA1537, TA1538, TA98 and
TA100, with and without metabolic activation. The metabolic activation
system (S-9 microsomal fraction) was obtained from the liver of male rats
induced with Aroclor 1254. The highest concentrations of bronopol tested
were 125 j^g and 62.5 /ig/plate, in the presence and absence of S-9,
14
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respectively. Concentrations of bronopol higher than those tested were
cytotoxic. The following positive controls were used: cyclophosphamide
(TA1535), neutral red (TA1537) and 2-aminofluorene (TA1538, TA98 and
TA100). Distilled water was the solvent for bronopol and dimethyl
sulfoxide (DMSO) for positive controls. This study 'Satisfies the
requirements for genetic effects, Gene Mutations. (MRID 40660902)
Bronopol was negative for mutagenicity in the V79 cell mutation
assay (Chinese hamster lung fibroblasts), with and without metabolic
activation, when tested at concentrations up to 8 /ig/mL, the maximum
allowed by cytotoxicity. The metabolic activation system (S-9 microsorhal
fraction) was obtained from the livers of male rats induced with Aroclor
1254. N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was used as a
positive control in the absence of S-9 and 7,12-dimemylbenz(a)anthracene
(DMBA) in the presence of S-9. Distilled water was the solvent for
bronopol and dimethyl sulfoxide (DMSO) was the solvent for the positive
controls. Mutagenic potential was evaluated by comparing the frequencies
of the 6-thioguanine (6-TG)-resistant mutants observed in the treated
cultures with those observed in the negative control (distilled water)
cultures. This study satisfies the requirements for genetic effects, Gene
Mutations. (MRID 40660903) ..
In the mammalian cells (human lymphocytes) in culture cytogenetic
assay, bronopol was hot clastogenic in the presence of the metabolic
activation system (S-9 microsomal fraction) and was clastogenic in the
absence of S-9, but only at 30 jig/mL, the highest concentration allowed by
cytotoxicity. Other concentrations of bronopol tested were 10 and 20
fig/mL without S-9 and 20, 30 and 40 /uig/mL with S-9. Positive controls.
used were mitomycin C (0.5 jig/mL) in the absence of S-9 and
cyclophosphamide (25 jig/ mL) in the presence of S-9. Distilled water was
a solvent for all test compounds and was also a negative control. The
observed dastogenicity (significant increases hi the percentage of cells with
aberrations, relative to the negative control values) was attributed by the
testing facility to formaldehyde, one of the degradation products of
bronopol and a known clastogen. Other degradation products of bronopol
were not identified. This study satisfies the requirements for genetic
effects, Structural Chromosomal Aberrations. (MRID 40660904)
Bronopol was negative hi the in vivo micronucleus assay, in which
male and female CD1 mice received single oral doses of bronopol (80 or
160 mg/kg of body weight) and then were sacrificed at 24, 48 and 72 hours
after dosing. At all sampling times, the bronopol-treated and negative
control mice had similar numbers of micronuclei per 1000 polychromatic
erythrocytes of femur bone marrow examined, per animal. The 160 mg/kg
15
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dose was the maximum tolerated dose (MTD), as judged by mortality (4/24
males and 4/24 females) and by reduced numbers of polychromatic
erythrocytes (indicative of a reduction in hemopoiesis) in some surviving
mice, 72 hours after treatment. The positive control, cyclophosphamide
(75 mg/kg), significantly increased the numbers of micronuclei in both
sexes. Sterile double-distilled water was.used as; solvent for the test
materials and was also a negative control. This study satisfies Guideline
requirements for genetic effects classified as Other Genotoxic Effects.
(MR1D 40660905)
g. Metabolism
The rat metabolism data for bronopol consist of four separate
studies conducted with male and female Sprague-Dawley rats. Animals
were treated by gavage with 14C bronopol (radiochemical purity: >95^
100%). In the first study animals received a single dose of 10 mg/kg. The
second study employed a higher dose of 50 mg/kg. Doses, higher the 50
mg/kg caused respiratory problems and death. The third study' s dose was
10 mg/kg (14 daily doses of nonradioactive, 100% pure, bronopol,
followed by one dose of 14C-bronopol). Urine, feces and CO2 were
collected for 7 days after dosing, at which time the rats were killed and the
tissues examined for radioactivity. Because, irrespective of the dose, most
of the administered 14C was excreted in urine (64-78% in 24 hours and 68-
83% in 7 days), urine was used for the identification of metabolites hi the
fourth study. Feces, CO2 and tissues represented minor routes of excretion
of 14C. Very little 14C was also detected in the whole blood and plasma.
From the results of these four studies the Agency concluded that
bronopol administered orally was rapidly absorbed and rapidly excreted by
the rats of both sexes, with urine being the major route of excretion. The
only metabolite identified in urine was BTS 23 913 (2-nitropropane-l ,3-
diol or desbromo-bronopol), accounting for 45-50% of the radioactivity
taken for analyses. The remaining radioactivity was not identified (one
radioactive peak and radioactivity not resolved into peaks). Unchanged
bronopol was not detected. (MRID 43289501)
h.
Reference Dose
The Agency's Office of Pesticide Programs, Reference Dose
(RfD)/Peer Review Committee recommended that the RfD for bronopol be
established at 0.1 mg/kg/day. This value was based on the systemic NOEL
of 10 mg7kg/day from the rat chronic feeding study (MRTOs 00098386,
00115645 or 00138766) and an uncertainty factor (UF) of 100 (10 for
interspecies and 10 for intraspecies variability). Decreased food
16
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2.
consumption and body weight gain, and squamous metaplasia and
inflammation in ducts of salivary glands were observed at the next level
tested, 40 mg/kg/day. (RfD Peer Review Committee Report, June 12,
1995) Although bronopol has no food uses at this time, the RfD has been
established because the data base is available and because of possible long-
term exposure to bronopol containing products.
It should be noted that this class of chemicals (disinfectants,
microbiocides, microbiostats, sanitizers) has not been reviewed by the
FAO/WHO Joinl Committee on Pesticide Residues (JftfPR).
i. Toxicological Endpoints of Concern
EPA believes the appropriate lexicological ehdpoint for assessing
short-term (1-7 days) or intermediate-term (7-90 days) occupational or
residential exposure from bronopol is the 40 mg/kg/day NOEL for
maternal and developmental toxicity which was observed in the rabbit
developmental toxicity study. (MRJJ) 42319601) Decreased maternal body
weight gain and food consumption during most of the gestation period and
several developmental effects were observed in that study at 80 mg/kg/day,
theLQEL. .
, The lexicological endpoiht for assessing chronic occupational
exposure is the NOEL of 10 mg/kg/day from the 2-year rat feeding study.
This study was also used to establish the RfD.
In the absence of dermal absorption data (due lo the corrosive
properties of bronopol), NOELs. derived from oral studies were used
directly and without modification to estimate NOELs for dermal exposure.
Therefore, the Agency assumed a default of 100% dermal absorption.
Exposure and Risk Assessment
a. Dietary Exposure and Risk Assessment
Currently there are no registered food uses of bronopol, therefore,
a dietary exposure and risk assessment is not needed.
b. Occupational Handler Exposure Assessment
(1) Occupational Exposure Scenarios
The Agency conducts an occupational exposure assessment
for a pesticide active ingredient if (1) certain lexicological criteria
17
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are triggered and (2)-there is potential exposure to handlers
(mixers, loaders, applicators) during use or to persons entering
treated sites after application is complete. The Agency believes this
is the case from the use of bronppol products. Above, the Agency
described its conclusions regarding toxicology end points of concern
for bronopol. Below there is discussion of potential exposures from
the use of these products.
The Agency has determined that there is.a potential for
exposures to mixers, loaders, applicators, or other handlers from
applications of bronopol containing products in commercial and
industrial settings. The Agency has identified two levels of handler
exposures:
primary handlers — persons or handlers using
(mixing, loading, applying) end-use bronopol
products;
.secondary handlers — persons using (mixing,
loading, applying or otherwise handling) products,
such as paints and adhesives, to which a bronopol
product has been added.
' . '
Based on the use patterns, the Agency has identified four
major bronopol exposure scenarios for primary occupational
handlers: (1) metering-pump applications with the soluble
concentrate liquid formulation, (2) open-pour applications with the
soluble concentrate liquid formulation, (3) open-pour applications
with the soluble concentrate solid formulation, and (4) application
of solid tablets and pellets. The application of paint treated with
bronopol is considered by the Agency the worse-case for secondary
handler exposure and risk.
(2) Occupational Exposure Estimations
Exposure data specific to bronopol are unavailable nor are
there surrogate exposure data for all use-patterns. However, the
exposure scenarios selected for assessment are representative of
reasonable worst-case exposures to bronopol. To estimate unit
exposure (UE) and actual daily exposure (ADE), the Agency relied
on surrogate data from a study (amended 1992) submitted by the
Chemical Manufacturers Association (CMA) for antimicrobial
.pesticide products. Based on these data, inhalation exposure is
believed to be minimal for the scenarios evaluated. Actual daily
18
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exposure (ADE), which is used to estimate risk, is calculated using
the following formula:
ADE =
unit exposure (jigm/lb a.i. X application rate (Ib. a.i./A.)
body weight (kg) . '
The Agency's assumptions for mixers and loaders include
both short-term (1-7 days per year) and intermediate-term (7-90
days per year) exposure as a reasonable worst-case estimate. The
Agency also assumes dermal absorption is 100% and body weight
is 60 kg.
Estimates for short and intermediate-term exposures from
the above equation and assumptions are presented in Table 2 for the
different occupational primary handler scenarios. The estimates
suggest occupational exposures of bronopbl to handlers are low
(£0.127 mg/kg/day) except for the liquid soluble concentrate pour
applications for cooling water systems (2.849 mg/kg/day).
19
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Table 2: Short and Intermediate-Term Exposure's and Risks (MOEs) for Handlers from uses of Bronopol
Application Method
Metered Pump
Soluble Concentrate
Liquid
Open Pouring
Soluble Concentrate
Liquid
Open Pouring
'Soluble Concentrate
Solid
Place Solid (tablets
and package)
Setting
Oil Well Mud Packer Fluid
Oil Well Injection Fluid
Paint Manufacturing
Pulp and Paper
Cooling Water Systems
Metal Working Fluids
Oil Well Mud Packer Fluid
Cooling Water Systems
Paint Manufacturing-
Metal Working Fluids
OU Well Mud Packer Fluid .
Cooling Water Systemls
Paint Manufacturing
Metal Working Fluids
Laboratory Water Recirculating Waterbaths
Industrial and commercial air conditioning and humidifying
systems ,
ADE
(mg/kg/day)
.< 0.001
0.0235
< 0.001
0.00339
0.02507
0.02264
0.00877
2.849
0.00975
0.00927
0.0273
0.12741
0.03185
0.03792
0.06233
<,0.001
MOE
40,000.00
1,702.13
40,000.00
il,799.41
1,595.53
1,766.78
4,561.00
14.04
4,102.56
4,314.99
1,465.20
313.95
1,255.89
1,054.85
641.75
40,000.00
For the secondary handler exposure scenario (painters) the-
Agency has no bronopol specific exposure data for painter
exposure. Surrogate exposure data were used from the Pesticide
Handlers Exposure Database. In this database gloves were not worn
and, the Agency assumes from bronopol product label directions for
use that the paint contains 500 ppm of bronopol. Also assumed is
a painter exposure frequency of 250 times per year which is
considered chronic exposure. Estimated exposures were calculated
for occupational painters and are presented in Table 3.
20
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Table 3. Chronic Term Exposures and Risk (MOE) to Painters from Bronopol-Treated Paint
! .. "Setting ^-.
Paint Brush
, * ^"'-PE1 " " .'
" - ' l mg/lb ai"r '
290 (dermal)
single layer, no gloves
38 (dermal)
single layer, chemical
resistant gloves (used
90% PF)
0.57 (inhalation)
• Jb/ai/day2
0.025
0.025
f , , t
0.025
BW(kg)
60
60
60
Actual Daily^Exposure
(mg/kg/day)
0.12
0.016
2.4x10*
^MOE4
333
2,500
N/A5
Dermal grade A,B,C from PHED.
n=15 medium confidence. Inhalation grade C, n= 15 medium confidence
500 ppm (bronopol). One gallon paint equal to 10 Ibs
3 ADE (mg/kg/day) = UE x (Ib ai used per day) / 60 kg. " v
4 MOE - NOEL /ADEx dermal absorption ' / .
Inhalation exposure is very small relative to the dermal exposure.and therefore MOEs for the inhalation component were not estimated
(either alone or combined with the dermal.)
c. Occupational Handler Risk Assessments
To estimate risks from exposures to bronopol, the Agency
compared the margin of exposure (MOE) between the NOELs from the
toxicological end points of concern and the estimates of exposure (ADE).
Where 40 mg/kg/day is the NOEL for short-term and intermediate-term
exposures from the developmental toxicity study described above, the
Agency calculated occupational exposures as presented in Table 2. /The
following equation was used for estimating the risk, expressed as a margin
of exposure (MOE).
MOE = NOEL 40 mg/kg/day
ADE ADE
As Shown in Table 2, the calculated MOEs for the short and
intermediate-term exposure scenarios are very high, the application
scenario of pouring liquid concentrates into cooling water systems. Here
the MOE is 14. Use of a metering pump delivery system for the liquid
application of bronopol products to this use site would adequately mitigate
this risk (see Sections TV and V). .
Using the assumptions described above for secondary occupational
exposure and the chronic endpoint NOEL of 10 mg/kg/day the MOEs are
greater than 100 for painters (Table 3). Since the MOEs for painter
exposure do riot suggest adverse risk and this use represents the worst case
21
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chronic exposure scenario, assessments for other chronic scenarios were
not conducted.
' *
d. Occupational Post-Application Exposure and Risk
The Agency believes there are. potential exposures following
applications of bronopol containing end-use products in commercial and
industrial settings. Two levels of post-application exposures have been
identified. The first is primary post-application exposures ~ persons in and
near areas where bronopol products are being or have recently been
applied. In these areas there may be airborne exposures to bronopol,
resulting hi dermal and inhalation exposures from mists or steams. The
key exposure scenarios include: (1) exposures following applications of
bronopol to open vats of liquids, such as paper-pulp, adhesives, coatings,
emulsions, and paints; and (2) exposures to persons maintaining equipment,
such as water systems and other industrial equipment, which contain a
product treated with bronopol. The other occupational post-application
exposure is secondary exposure to persons occupying areas recently painted
with bronopol-containing paint and exposures hi areas where bronopol
containing paper products are being manufactured. The Agency's concerns
about potential post-application exposures to bronopol are minimal because
the MOEs for occupational exposure are not exceeded (except for the open
pouring of liquid concentrates in cooling water systems) and even less
exposure would be expected during post-application.
e. Residential Exposure and Risk .
At this time there are no end-use pesticide products containing
bronopol that are intended for homeowner use. Therefore, there is no
. concern for the homeowners as primary handlers.
However, based on the use patterns, the Agency has identified two
potential secondary homeowner handler exposure scenarios. They are (1)
exposure while handling bronopol-containhig paint, and (2) exposure while
handling bronopol-containing adhesives. The Agency has also identified
two bronopol exposure scenarios for secondary homeowner post-application
exposures: (1) exposures while occupying areas recently painted with
bronopol-containhig paint, and (2) exposures while occupying areas where
bronopol-containing adhesives have been used. Based on the occupational
painter risk assessment as a worst case scenario, EPA believes risk
associated with these residential exposures are not of concern.
22
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f. Formaldehyde Exposure and Risk
The Agency has also looked at potential formaldehyde exposure to
products containing bronopol since formaldehyde has been identified as a
degradate of bronopol under aqueous alkaUne conditions. However, the
Agency is not concerned about handlers or post-application exposures to
, formaldehyde because of bronopol1 s slow decomposition rate. When
mixed with water the half-life of bronopol decomposition to formaldehyde
is 18 years atpH4; 1.5 years at pH 6; and 2 months at pH.8 at 20°. Also,
post-application settings are addressed for formaldehyde by. the
Occupational Safety and Health Administration(OSHA). OSHA has a
comprehensive workplace standard for formaldehyde for the protection of
workers in the industrial setting due to formaldehyde release in the
workplace. The OSHA formaldehyde standard was established as a rule in
May 1992, and set a permissible exposure level (PEL) of 0.75 ppm in the
workplace. The standard also prescribes that certain actions should be
taken if monitoring shows levels of 0.50 ppm. This standard requires
monitoring before workers enter' the premises following use of
formaldehyde, or when potential ambient formaldehyde is generated from
other chemicals.
s , I . ,
C. Environmental Assessment
1. Ecological Toxicity Data .'.-..
• \ - ~ ~ • - - ; * '
The Agency has adequate data to assess the hazard of bronopol to nontarget
terrestrial and aquatic organisms for the uses specified in the RED.
a. Toxicity to Terrestrial Animals
(1) Birds, Acute and Subacute
In order to establish the toxicity of bronopol to birds, the
following tests are required using the technical grade material: one
avian single-dose oral (LD50) study on one species (preferably
mallard or bobwhite quail); one subacute dietary study (LC50) on
one species of waterfowl (preferably the mallard duck) or one
species of upland game bird (preferably bobwhite quail or ring-
necked pheasant). Tables 4 and 5 summarize the available data for
avian acute Oral toxicity and avian subacute dietary toxicity.
23
-------
• s " " "..'." - ,„»•,<; ••*<•»•"•'..'/•,•,•••> K •• - •* < 7
*Table4. * -Avian Acute Oral Toxidly Findings ^ ,' "
Species
Mallard
%A.I.
99.4
LDjomg/kg
509.5
MRIDNo.
00104689
Toxicity Category
slightly toxic
;Table 5. Avian Subacnte Dietary Toxieity Findings „ V*
Species
Northern Bobwhite'
Mallard
% A.I.
100
100
LCjo pptn
4487.6
> 10,000
MRIDNo.
00148526
00148941
Toxicity Category
Slightly toxic
Practically nontoxic
Bronopol is slightly toxic to avian species on an acute oral
basis and slightly toxic to practically nontoxic on a subacute dietary
basis. The guideline requirements are fulfilled. (MRID 00104689,
00148526,00148941)
b. Toxicity to Aquatic Animals .
(1) Freshwater Fish
In order to establish the toxicity of bronopol to freshwater
fish, the minimum data required on the technical grade of the active
ingredient is one freshwater fish toxicity study. The study should
use a coldwater species (preferably the rainbow trout) or a
warmwater species (preferably the bluegill sunfish). Available data
for acute fish toxicity are summarized in Table 6.
' ' -, "•« '»**""• * "r""^^ -''''' j'f J'~^J-"'' *"' ^ -f * „ ! /
'Table 6. - - Fr^hwatoFisttA^eToxidferJKnaings - - '•** " ~"
Species
Rainbow trout
Bluegill sunfish
%A.I.
100
99.7
LCjo ppm a.i.
41.6
36.1
MRTONo.
00148563
00148940
Toxicity Category
Slightly toxic
Slightly toxic
The results of the 96-hour acute toxicity studies indicate that
bronopol is slightly toxic to fish. The guideline requirements are
fulfilled. (MRTOs 00148563, 00148940)
24
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(2) Freshwater Invertebrates
A freshwater aquatic invertebrate toxicity test is a minimum
requirement to determine pesticide hazard to freshwater
invertebrates. This is preferably done using either first instar
Daptana magna or early instar amphipods, stoneflies, mayflies, or
midges. Table 7 summarizes the data available for freshwater
invertebrates.
Table 7* I "- ' * ''Freshwater Invertebrate Toxicity Findings „ * ' -\ -
Species
Daphnia magna
%A.I.
99.4
ECgo (mg/1)
1.4
MRIDNO.
0098404
Toxicity Category
moderately toxic
The data are sufficient to characterize bronopol as
moderately toxic to aquatic invertebrates. The guideline
requirement is fulfilled. (MRTO 0098404)
(3) Estuarine and Marine Animals
Acute toxicity testing with estuarine and marine organisms
is required when an end-use product is intended for direct
application to the estuarine/marine environment hi significant
concentrations. The aquatic nonfood industrial (off recovery
drilling mudsf pulp/paper mill water and secondary oil recovery
injection water) uses of bronopol may result hi exposure to the
estuarine and marine environment.
The requirements under this category include a 96-hour LC50
for an estuarine fish, a 96-hour LC50 for shrimp, and either a 48-
hour embryo-larvae study or a 96-hour shell deposition study with
oysters; Table 8 summarizes available estuarine/marine acute
toxicity findings.
\ *" v , *' <* n .!"*"*""""* ^s -V1 """ y ¥ k w^ ~ ^ ^^ ^ * J s f K-t^ * I \1_<
T^leS, - ' "'- ' ^^F^anneTRferine^cuteTosacifyJIndings
Species
Eastern oyster (embryo larvae)
Mysid Shrimp
' Sheepshead minnow
%'A.I.
99.7
99.7
99.7
LCjg/ECj, (ppmai)
0.77
5.9
59.6
MRTONo.
00148979
- 00150674
00163176
V
Toxicity Category
Highly toxic
Moderately toxic
Slightly toxic •
25
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2.
There is sufficient information to characterize bronopol
from moderately toxic to highly toxic to estuarine/marine
invertebrates. It is slightly toxic to estuarine/marine fish. The
guideline requirements are fulfilled. (MRIDs 00148979, 00150674,
00163176). ,
Environmental Fate
The environmental fate database for bronopol is adequate for reregistration
purposes. Under current Agency policy for microbiocides, the environmental fate
data requirement is minimal - only a hydrolysis study is required. The hydrolysis
study is satisfactory. In addition, the Agency has a partially satisfactory photolysis
study; physical and chemical properties (product chemistry).
a. Environmental Fate Assessment
From the limited data and summary information available, the
Agency infers that bronopol would have a relatively short half-life upon
release into the environment. This conclusion is based on the compound's
photoreactivity in water (its activity decreases by one-half in two days),
high number of reactive sites, and presumptive degradation by microbes.
The Agency does not have specific data for mobility of bronopol in
soil; however, the Agency does not anticipate ground water contamination
from the use of bronopol. Although bronopol has high water solubility
(approximately 25% w/v), high solubility hi polar solvents, low solubility
in nonpolar solvents, and favorable partitioning into water, the Agency
believes that bronopol's short-lived environmental persistence reduces the
potential for groundwater contamination.
Bronopol is stable to hydrolysis under normal conditions.
However, at warmer temperatures and/or higher pHs (as encountered in
some industrial applications or under atypical environmental conditions),
rapid hydrolysis may occur. Under these high temperatures and pHs,
hydrolysis products include formaldehyde and lesser amounts of other
degradates.
Judging from its low octanol/water ratio (1.5/1) and high solubility
in water, bronopol is not expected to bioaccumulate. Accumulation
reportedly does not occur in tested mammals and metabolism is also
reported to be rapid and complete, as described above.
26
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b. Environmental Fate and Transport
(1) Hydrolysis
An adequate hydrolysis study exists. Hydrolysis is strongly
correlated with temperature and pH. Hydrolysis may or may not
occur appreciably, depending on conditions. An acceptable study,
conducted under conditions different from the Agency's present
testing guidelines, concluded that bronopol is1, stable against
hydrolysis in "typical" natural settings. At elevated temperatures
(30, 40, 50* and 60°C), in ambient laboratory light and at
concentrations of 2000 ppm or higher, the half-life was extrapolated
to be the following at 20°C: about 18 years at pH 4, about 1.5
years at pH 6, and approximately 2 months at pH 8. At higher
temperatures and/or pHs, as may occur in industrial applications,
hydrolysis is greatly accelerated. At 60°C (140°F), half-lives
range roughly from 4 days at pH 4 to only 3 hours at pH 8. Under
accelerated conditions, degradation is extensive, and formaldehyde
is a major hydrolysate. Other degradates produced under these
circumstances are 2-hydroxymethyl-2-nitroprppane-l,3-diol (tris);
2-bromo-2-nitroethanol; unidentified products which were possibly
polymeric; bromide; nitrite (not nitrate); and other trace products
such as aliphatic nitro compounds and lightweight gases, but not
carbon dioxide. (MRTOs 00164535 and 00163783)
(2) Degradation .
A partially satisfactory photodegradation in water study
indicates that bronopol rapidly photodegrades at pH 4 under
continuous xenon irradiation; approximately one-half of its activity
remained after about 24 hours. An equivalent exposure time under
natural sunlight would be approximately 2 days (assuming 12 hours
each of light and dark). Tris (2-hydroxymethyl-2-nitropropane-l,3-
diol), also named tris-hydroxymethyl-nitromethane, a tentatively
identified major degradate (up to about 60 percent), which appears
to further degrade, but at a slower rate. Another major, but
unidentified, "relatively polar" product (component "B") steadily
increased, and at the end of the .168 hour (one week) study was up
to about 30 percent of the dose. Component "B" was not the
putative degradate, 2-bromo-2-nitroettianol. Steadily increasing
levels of labeled carbon dioxide derived from the central carbon
atom of bronopol indicate that at least one reaction leads to
extensive degradation. Although carbon dioxide increased in
parallel with unknown component '"B," formation of component
27
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"B" and carbon dioxide appears to occur by separate pathways.
(MRID 429413-03)
3. Environmental Exposure and Risk
Aquatic nonfood industrial uses of bronopol containing products can result
in discharge of effluent to surface waters. These discharges .may adversely affect
aquatic life in the receiving stream waters. As described above bronopol is
moderately toxic to freshwater invertebrates; slightly toxic to freshwater fish;
moderately to highly toxic to estuarine/marine invertebrates; and slightly toxic to
estuarine/marine fish.
While the hazard to aquatic organisms from bronopol has been
characterized, a quantitative risk assessment has not been conducted because the
potential risks to aquatic environments are regulated under the EPA Office of
Water, National Pollution Discharge Elimination System (NPDES) permitting
program. The Agency currently requires' that labels for all bronopol products
require that discharges to aquatic environments comply with an NPDES permit.
The fuel use of bronopol may be associated with periodic releases into the
environment based on purging of the storage tanks. This terrestrial use may result
in minimal to no exposure to the environment. All bronopol product labels are
required by the Agency to have language that is consistent with disposal of
unwanted treated fuel or bottom waters that complies with any applicable federal
laws
4. Endangered Species
( .' • • .
The Agency does not anticipate any exposure of concern to fish and
wildlife, providing that all bronopol products are labeled, handled, and applied as
specified in this document and product labels require that discharges to the
environment comply with NPDES permitting requirements and Federal laws.
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 reregistration. The Agency has previously identified and
required the submission of the generic (i.e. active ingredient specific) data required to
support reregistration of products containing bronopol 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 bronopol. However, the
28
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Agency is requiring data for compliance purposes on occupational exposure to workers
with a Data Call-In that was issued in September 1995. Appendix B identifies the generic
data requirements that the Agency reviewed as part of its determination of reregistration
eligibility of bronopol, and lists the submitted studies that the Agency found acceptable.
The data identified in Appendix B were sufficient to allow the Agency to assess the
registered uses of bronopol, as specified in this document, and to determine that bronopol
can be used without resulting in unreasonable adverse effects Jo humans and the
environment. The Agency therefore finds that all products containing'bronopol as the-
active ingredients are eligible for reregistration. The reregistration of particular products
is addressed hi Section V of this document.
The Agency made its reregistration 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 bronopol, as specified in this
document, 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 bronopol, if new information comes to the
Agency's attention or if the data requirements for registration (or the guidelines for
generating such data) change.
B. Determination of Eligibility Decision
1.
Eligibility Decision
Based on the reviews of the generic data for the active ingredient bronopol,
the Agency has sufficient information on the health effects of bronopol and on its
potential for causing adverse effects hi fish, wildlife and the environment. The
Agency has determined that bronopol products, labeled and used as specified in
this Reregistration Eligibility Decision document, will not pose unreasonable risks
to humans or the environment as long as label restrictions prescribed hi this RED
are followed. Therefore, the Agency concludes that products containing bronopol
for all currently registered uses are eligible for reregistration.
2. Eligible and Ineligible Uses
The Agency has determined that all currently registered uses of bronopol,
as modified in this document, are eligible for reregistration.
29
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C. Regulatory Position
The following is a summary of the regulatory positions and rationales for bronopol.
Where labeling revisions are imposed, specific, language is set forth in Section V of this
document.
1. Occupational Risk Mitigation Measures/Labeling Rationale
a. Personal Protective Equipment/Engineering Controls
For each bronopol end-use product, PPE requirements for pesticide
handlers are being set during reregistration for the following reasons:
The Agency is requiring PPE for occupational handlers of bronopol
in the loading of (1) liquid bronopol end-use products using open-pouring
and metering-pump techniques and (2) dry (pellets, tablets, crystals, or
flakes) bronopol end-use products using open-pouring and hand-placement
techniques. PPE (long sleeved shut, long pants, chemical resistant gloves,
socks and shoes) were worn by the handlers in the CM A studies that were
used to estimate exposures. This requirement will mitigate risks to
occupational workers.
The Agency is also concerned about occupational exposure in the
cooling water systems use where open pouring of liquid bronopol end-use
products can occur. When using the Agency established method to calculate
margin of exposure (MOE), this use pattern exceeds the Agency's
acceptable levels of exposure. In Section V the Agency outlines the specific
application restriction of a metering pump system to mitigate potential risk
to occupational workers for this use.
Post-application entry restrictions are not being established at this
time for occupational uses of bronopol end-use products, because the
Agency believes the potential exposure to bronopol would be less than that
to handlers due to dilution, industrial processes, and the stability or slow
degradation of bronopol in products that contain it. Additionally, the
Agency is not establishing PPE for people applying bronopol treated
products (such as paint and adhesives) since exposures are expected to be
less than those for handlers applying bronopol end use products.
2. Aquatic Risk Mitigation/Labeling Rationale
The Agency believes that potential hazards to aquatic organisms could exist
from the industrial uses of bronopol. All bronopol product labels are required by
the Agency to have language that is consistent with NPDES permitting
30
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requirements when direct effluent discharges to aquatic environments occur and
that disposal of unwanted treated fuel or bottom waters complies with any
applicable federal laws. These environmental risk reduction measures are
appropriate to retain for bronopol products.
3. Other Labeling Requirements
The Agency is requiring additional use and safety information to be placed
on the labeling of all end-use products containing bronopol to afford supplemental
protection to handlers. For the specific labeling statements, refer to Section V of
this document.
V. ACTIONS REQUIRED OF REGISTRANTS
This section specifies the data requirements and responses necessary for the reregistration
of both manufacturing-use and end-use products.
A. Manufacturing-Use Products
1. Additional Generic Data Requirements
The generic data base supporting the reregistration of bronopol for the
above uses has been reviewed and determined to be substantially complete. The
following generic data were required in a September 1995 Data Call-In.
Handler Studies - . ,
Any bronopol registrant who has not satisfied generic data requirements for
Guidelines 233 and 234, Dermal and Inhalation Exposure, must do so to meet the
requirements of reregistration. Failure to do so will result in suspension of affected
product registrations under FIFRA, Section 3(c)(2)(B). Compliance is also
necessary for product reregistration. Compliance with these generic data
requirements can be met in one of two ways. First, affected registrants can make
an irrevocable offer to pay compensation to owners of the existing data from the
CMA study. These data are MRIDs 41412201, 41742601, and 42587501.
Second, affected registrants can offer to conduct and submit new studies. The
Agency has issued a DCI to affected registrants in which both options are
provided.
31
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B. End-Use Products
1. Additional Product-Specific Data Requirements
Registrants of end-use product registrations which are subject to generic
data requirements, and who have not satisfied the generic data requirements for the
above handler exposure studies must do as described above.
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.
2. Labeling Requirements for End-Use Products
a. PPE/Engineering Control Requirements for Pesticide Handlers
For sole-active-ingredient end-use products that contain bronopol, the
product labeling must be revised to adopt the handler personal protective
equipment/engineering control 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 bronopol, the
handler personal protective equipment/engineering control 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.
Minimum (Baseline) PPE/Engineering Control Requirements — EPA
is establishing active ingredient-based minimum (baseline) PPE/engineering
control requirements for bronopol end-use products that are intended for
occupational use. The minimum (baseline) PPE for such occupational uses
of bronopol end-use products are:
32
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"Applicators and other handlers must wear:
—long-sleeve shirt and long pants,
—socks plus shoes, and
-chemical-resistant gloves."*
* For the glove statement, use the statement established for bronopol
through the instructions in Supplement 3 of PR Notice 93-7.
For end-use products classified as toxicity category I or n for eye
irritation, protective eyewear is also required.
For liquid product formulations applied to cooling water systems the
following engineering control restriction is required on product labels.
1. "Do not apply by open pouring of liquid to cooling water
systems; a metering pump delivery system is required for this use
and application method."
b. Other Application Restrictions
Other application restrictions for bronopol product labels are:
1. For all end-use products: "Do not apply this product
in a way that will' contact workers or other persons."
2. For all end-use products: "Follow manufacturer's
instructions for cleaning/maintaining PPE. If there are no such
instructions for washables, use detergent and hot water. Keep and
wash PPE separately from other laundry."
3. For liquid end-use products only: "Discard clothing or other
absorbent materials that have been drenched or heavily
contaminated with this product's concentrate. Do not reuse them."
c. User Safety Recommendations
Add the following user safety recommendations to labels of all
bronopol end-use products: ;
1. "Users should wash hands before eating, drinking,
chewing gum, using tobacco, or using the toilet."
2. "If pesticide gets inside clothing remove clothing
immediately, wash thoroughly, and put On clean clothing."
33
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3. "Users should remove PPE immediately after
handling this product. Wash the outside of gloves before
removing. As soon as possible, wash thoroughly and change
into clean clothing."
d. Effluent Discharge and Disposal Labeling Statements
To reduce environmental risk from bronopol discharge and disposal,
product labels must continue to have the statements pertaining to effluent
discharge under the NPDES permitting system (refer to PR Notice 93-10
or 40s CFR 152.46(a)(l)) and disposal under any applicable federal laws.
e.
Directions for Use
Registrants must specify on labeling the complete directions for use
for each use pattern: site of application, type of application, timing of
application, equipment used for application, and the rate of application
(dosage).
f . Clarification of Oil/Gas Drilling Mud Packer Fluids Use
To clarify the intent of the oil recovery drilling muds/packer fluids
use, as an aquatic or terrestrial non-food use pattern, the following
statements must be added to the labels. For bronopol products labeled for
this use and the registrant intends applications to be limited .to terrestrial
sites, add the following:
"For use in terrestrial wells only. Do not apply in marine
and/or estuarine oil fields." .
><•-.') •
For products intended for applications for aquatic sites add the
following:
"For use in off-shore Wells only." '
For use in both terrestrial and aquatic sites add:
"This product may be used in terrestrial and off-shore oil
drilling muds and packer fluids."
3. Existing Stocks
j ' t
t • • • . ' _
Registrants may generally distribute and sell products bearing old labels/labeling
for 26 months from the date of the issuance of this Reregistration Eligibility Decision
34
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(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.
The Agency has determined that registrants may distribute and sell bronopol
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 seller distribute.
35
-------
36
-------
VI. APPENDICES
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GUIDE TO APPENDIX B
Appendix B contains listings of data requirements which support the reregistration for
active ingredients within the case bronopol covered by this Reregistration Eligibility Decision
Document. It contains generic data requirements that apply to bronopol 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 National
Technical Information Service, 5285 Port Royal Road, Springfield, VA 22161 (703) 487-4650.
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 (MRH>) number, but may be a "GS" number if no MRID number has been
assigned. Refer to the Bibliography appendix for a complete citation qf the study.
64
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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, hi 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 hi 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 "MRTO 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 hi the review may be preceded by a nine character
temporary identifier. These entries are listed after all MRTO 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 hi the document. When the date appears as (19??),
the Agency was unable to determine or estimate the date of the document.
68
-------
Tide. 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.
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)
(2)
(3)
(4)
Submission date. The date of the earliest known submission appears
immediately following the word "received."
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.
Submitter. The third element is the submitter.
defaulted to the submitter, this element is omitted.
When authorship is
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.
69
-------
BIBLIOGRAPHY
MRID
CITATION
00098384 Hunter, B.; Batham, P.; Heywood, R.; et al. (1973) Bronopol Oral Toxicity to
Rats; Repeated Administration for 13 Weeks: BTS34/73268. (Unpublished study
received Mar 31, 1982 under 47374-1; prepared by Huntingdon Research Centre,
England, submitted by Inolex Chemical Co., Chicago, HI.; CDL:247195-B)
00098386 Hunter, B.; Baiham, P.; Heywood, R.; et al. (1976) Bronopol Toxicity and
.Tumorigenicity Study in Rats by Administration in the Drinking Water for 104
Weeks: BTS51/75719. (Unpublished study received Mar 31, 1982 under 47374-1;
prepared by Huntingdon Research Centre, England, submitted by Inolex Chemical
Co., Chicago, 111.; CDL:247197-A)
00098387 Hunter, B.; Graham, C.; Prentice, D.E. (1975) Bronopol Potential Local and
Systemic Tumorigenic Effects in Repeated Dermal Application to Mice (Final
Report 0-80 Weeks): BTS 43/74761. (Unpublished study received Mar 31, 1982
under 47374-1; prepared by Huntingdon Research Centre, England, submitted by
Inolex Chemical Co., Chicago, HI.; CDL:247197-B)
00098396 Inolex Chemical Company (1976) Toxicity of Lexgard Bronopol to Laboratory
Animals.. (Compilation; unpublished study received Mar 31, 1982 under 47374-1;
CDL:247193-B; 247194)
00098397 Bums, R.; Berczy, Z.S.; Hague, P.H.; et al. (1971) Acute Inhalation Toxicity of
Bronopol to the Rat: 3878/71/36. (Unpublished study received Mar 31, 1982
under 47374-1; prepared by Huntingdon Research Centre, England, submitted by
Inolex Chemical Co., Chicago, HI.; CDL:247193-C) '
00098398 Maibach, H.I. (1977) Dermal sensitization potential of
2-Bromo-2-nitropropane-l,3-diol (Bronopol). Contact Dermatitis 3:99.
. (Also-In-unpublished submission received Mar 31, 1982 under 47374-1;
submitted by Inolex Chemical Co., Chicago, 111.; CDL: 247193-D)
00098399 Rivett, K.F.; Chesterman, H.; Skerrett, K.; et al. (1973) Boots: Bronopol Oral
Toxicity Study in the Beagle Dog (Initial Study and Repeated Dosage for 13
Weeks): BTS29/7336 & 73419. (Unpublished study received Mar 31, 1982 under
47374-1; prepared by Huntingdon Research Centre, England, submitted by Inolex
Chemical Co., Chicago, HI.; CDL:247194-A)
i
00098401 Davies, R.D.; Halliday, J.C.; Street, A.E.; et al. (1973) Effect of Repeated
Administration of Bronopol to the Skin of Rabbits for Three Weeks:
70 .
-------
BIBLIOGRAPHY
MRID
CITATION
BTS42/73549. (Unpublished study received Mar 31, 1982 under'47374-1;
prepared by Huntingdon Research Centre, England, submitted by Inolex Chemical
Co., Chicago, 111.; CDL: 247194-C) .
00098404 Williams, T.D.; Thompson, R.S.; Hill, R.W. (1981) Determination of the Acute
Toxiciry of Myacide BT to~Daphnia magna—,: Brixham Report No. BL/B/2128.
(Unpublished study received Mar 31, 1982 under 47374-1; prepared by Imperial
Chemical Industries PLC, England, submitted by Iholex Chemical Co., Chicago
•HI'.; CDL: 247196-D)
00104689 Fink, R.; Beavers, J.B.; Joiner, G. (1981) Final Report: Acute Oral
LD50-Mallard Duck: Myacide BT: Project No. 137-114. (Unpublished study
received Mar 31, 1982 under 47374-1; prepared by Wildlife International Ltd.,
submitted by Inolex Chemical Co., Chicago, 111.; CDL:247196-A)
00108808 Inolex Chemical Company (1973) Chemistry Data on Bronopol. (Un-published
study received Mar 31, 1982 under 47374-1; CDL: 247192-A; 247196)
00115645 Hunter, B.; Batham, P.; Heywood, R.; et al. (1976) Bronopol Toxicity and
Tumorigenicity Study in Rats by Administration in the Drinking Water for104
Weeks: BTS 51/75719. (Unpublished study received Oct 15, 1.982 under 47374-1;
prepared by Huntingdon Research Centre, Eng., submitted by Inolex Chemical
Co., Chicago, IL; CDL:248545,A)
' ? , . •• "- •
00138755 Smithson, A. (1984) Bronopol: Data on Individual Animals in Toxicity Studies:
Report No. TXA 83082. (Unpublished study received Mar 7; 1984 under
33753-1; submitted by Boots Co. LTD., Nottingham, ENG; CDL:252631-A)
00141875 . Inolex Chemical Co. (1982) Bronopol-Boots 2-Brdmo-2-Nitro-l,3-Propanediol
Product Chemistry. Unpublished study. 21 p.
00141876 Inolex Chemical Co. (1982) Myacide AS 2-Bromo-2-Nitro-l,3^Propanediol
Product Chemistry. Unpublished study. 21 p.
00148562 Roberts, N.; Fairley, C. (1984) The Subacute Dietary Toxicity (LC50) of
Bronopol to the Bobwhite Quail: HRC Report No. BTS 192/84697. Unpublished
Boots study HRC 227 prepared by Huntingdon Research Centre pic. 39 p.
71
-------
BIBLIOGRAPHY
MRID
CITATION
00148563 Hill, R. (1984) Bronopol: Determination of Acute Toxicity to Rainbow Trout,..:
BL/B/2490: Brixham Study No. M167/B. Unpublished study prepared by
Imperial Chemical Industries PLC. 26 p. .
00148940 Hill, R. (1984) Acute Toxicity to Bluegill Sunfish (Lepomis macro-chirus) (ICI):
Bronopol: Study No. M167/C. Unpublished study prepared by Imperial Chemical
Industries PLC Brixham Laboratory. Boots Co. Report No. TX 84106. 27 p.
00148941 Roberts, N.; Fairley, C.; Hakin, B. (1984) The Subacute Dietary Toxicity (LC50)
of Bronopol to the Mallard Duck: Boots Study No. HRC 228: BTS 191BT/84701.
Unpublished study prepared by Huntingdon Research Centre pic. 41 p.
00148979 Thompson, R. (1985) Determination of the Acute Toxicity to Larvae of the Pacific
Cn-ster (Crassostrea gigas): Brixham Study No. M167-F. Unpublished study
prepared by Imperial Chemical Industries. 28 p.
00150674 Hill, R. (1985) Bronopol: Determination of Acute Toxicity to Mysid Shrimps
(Mysidopsis bahia): Brixham Study No. M167/E. Unpublished study prepared by
Imperial Chemical Industries pic. 29p.
00160998 Liggett, M.; Parcel!, B, (1984) Irritant Effects on the Rabbit Eye of Bronules:
8422D/BTS 186/SE. Unpublished study prepared by Huntingdon Research Centre
pic. 17 p.
00163176 Linden, E.; Bengtsson, B.; Svanberg, 6. (1979) The acute toxicity of 78
chemicals and pesticide formulations against two brackish water organisms, the
bleak (Alburnus albumus) and the harpacticoid Nitocra spinipes. Chemosphere
(11/12):843-851.
00163783 Boots Co., Ltd (1986) pMyacide S-l: Response to EPA Letter Dated March 13,
1986: Product Chemistry and Hydrolysis. Unpublished compilation. 63 p.
00164535 Crampton, E,. (1986) Bronopol - Hydrolysis Study. Unpublished study prepared
by The Boots Co. PLC. 33 p.
40660902 Everest, R.; Williams, C. (1986) Bronopol-Boots: In vitro Bacterial Mutagenicity
Testing: Proj. ID TX 86004. Unpublished study prepared by The Boots Company
PLC. 15 p.
72
-------
BIBLIOGRAPHY
MRID
CITATION
40660903
40660904
40660905
42319601
42648201
42941301
42941303
43289501
43530401
Everest, R.; O'Donovan, M. (1986) Bronopol-Boois: In vitro Mammalian Cell
Mutation Assay: Proj. ID TX 86043. Unpublished study prepared by The Boots
Company PLC 24 p.
Everest, R.; Williams, C. (1986) Bronopol-Boots: In vitro Human Lymphocyte
Clastogenicity Testing: Proj. ID TX 86049, Unpublished study prepared by The
Boots Company PLC 19 p.
Everest, R.; Williams, C. (1986) Bronopol-Boots: Micronucleus Assay in Mice:
Proj. ID TX 86001. Unpublished study prepared by The Boots Company PLC.
21 p. ; . ... ' •'/•.„• -: ' •' . . ..
Irvine, L. (1992) Bronopol: Oral (Gavage): Rabbit Developmental Toxicity
(Teratogenicity) Study: Lab Project Number: BON/3/R. Unpublished study
prepared by toxicol Laboratories, Ltd. 198 p.
Irvine, L. (1992) Bronopol: Oral (Gavage) Rabbit Development Toxicity
(Teratogenicity) Study: Lab Project Number: BON/3/R. Unpublished study
prepared by Toxicol Labs., Ltd. 200 p.
Alexander, B.; Stagg, S.; MacLean, K. (1991) Bronopol-Product Chemistry
Phase 4 Response: Dissociation Constant. Unpublished study prepared by Inveresk
Research International Ltd. 28 p. :
Jackson, R.; Hall, B.; Self, D. (1992) Bronopol-Environmental Fate Phase 4
Response: Photodegradation-Water. Unpublished study prepared by Inveresk
Research International Ltd. 71 p.
Glass, R.; Hewertson, S. (1993) Study of the Excretion, Distribution, and
Metabolism of Bronopol in the Rat: Lab Project Number: DT93077:
RD/RCG/SJH/763474: BHR/006. Unpublished study prepared by Boots
Pharmaceuticals. 252 p.
Colhns, C. (1986) Bronopol Boots: Acute Inhalation Toxicity Study-Rats: 4 Hour
Exposure: Lab Project Number: 4920-316/14: 316/14. UnpubUshed study
prepared by Hazleton Labs Europe^ Ltd. 51 p.
-------
BIBLIOGRAPHY
MRID
CITATION
43598701 Palmer, K. (1995) Bronopol: Oral (Gavage) Rat Developmental Toxicity Study:
Final Report: Lab Project Numbers: BON/9/R: TXO95007. Unpublished study
prepared by Toxicol Labs Ltd. 165p. .
43608501 Steele, C. (1994) Bronopol: Oral (Gavage) Rat Developmental Toxicity Dose
Ranging Study: Lab Project Number: TX94032: BON/8/93. Unpublished study
prepared by Boots Pharmaceuticals. 106 p.
74
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
OFFICE OF
PREVENTION, PESTICIDES
AND TOXIC SUBSTANCES
DATA CALL-IN NOTICE
CERTIFIED MALL
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 produces) containing this active ingredient. Within 90 days after you receive this Notice
you must respond as set forth in Section ffl 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
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 DJ-B); or , . '
Why you believe EPA should not require your submission of product specific
data in the manner specified by this Notice (see section ffl-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
2,
3.
75
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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).
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 in - 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 - Requirements Status and Registrant's Response Form
4 - EPA Batching of End-Use Products for Meeting Acute Toxicology Data
Requirements for Reregistration
5 - List of Registrants Receiving This Notice
6 - Cost Share, Data Compensation Forms and Confidential Statement of Formula
Form
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 youN
have product(s) containing the subject active ingredient.
SECTION E. DATA REQUIRED BY THIS NOTICE
H-A. DATA REQUIRED
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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.
II-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. v. '. .
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 hi 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)J.
n-D. REGISTRANTS RECEIVING PREVIOUS SECTION 3(c)(2)(B) NOTICES
ISSUED BY THE AGENCY"" • . . . ~~ H
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 m. 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
•"•••• ' •''••''- •".' - 77, '••'•'.' ••••..--•''.' . '
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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.
m-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).
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 IH-C. A discussion of options relating to
requests for data waivers is contained in Section ffl-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 flie 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 DI-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 oh the, Data
Call-in Response Form. Deletion of a use(s) and the low volume/minor use option are not valid
options for fulfilling product specific data requirements.
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3. Request for Product Specific Data Waivers. Waivers for product Specific data are
discussed in Section ffl-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.
m-C SATISFYING THE DATA REQUIREMENTS OF THIS NOTICE
If you acknowledge on the Data Call-In Response Form .that you agree tq 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 tune frames in the Requirements Status and Registrant's Response Form are the tune
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 tune 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
•- . :-. »• • 79' .''•'" .'•."•"'
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laboratory performing the testing. While EPA is considering your request, the original deadline
remains. The Agency will respond to your request hi writing. If EPA does not grant your
request, the original deadline remains., Normally, extensions can be requested only hi cases of
extraordinary testing problems beyond the expectation or control of the registrant. Extensions
will not be given hi submitting the 90-day responses. Extensions will riot be considered if the
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 hi Cost to Develop Data - Registrants may only choose
this option for acute toxicity data and certain efficacy data and only if EPA has indicated hi 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 hi the agreement to cost share by the registrant selecting this option. If you choose to enter
into an agreement to share hi 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 hi 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 ;f the parties cannot resolve
the terms of the agreement they may resolve their differences through binding arbitration.
Option 3. Offer to Share in the Cost of Data Development - This option only applies to
acute toxicity and certain efficacy data as described hi option 2 above. If you have made an offer
to pay hi 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
option) to exercise its discretion not to suspend your registration(s), although you do not comply
with 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 hi good faith sought and continues to seek to enter into a joint data
development/cost sharing program, but the other registrant(s) developing the data has refused to
accept your dffer. To qualify for this option, you must submit documentation to the Agency
proving that you have made an offer to another registrant (who has an obligation to submit data) .
to share hi the burden of developing that data. You must also submit to the Agency a completed
EPA Form 8570-32, Certification of Offer to Cost Share hi 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, hi addition to anything else, offer to share hi the burden of producing the data upon
terms to be agreed or failing agreement to be bound by binding arbitration as provided by FIFRA
section 3(c)(2)(B)(iii) 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.
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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
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: ~—
' •' • - . . " . . ! i , ' ' . ' ,"-,-'
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.(jX" 'raw data1 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 pf 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 data' 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
.- . '• '•-.'' 81 - • . ' '• •-'. .• • '.'•"'
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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
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 tune 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 hi Option 4 above, apply to all
data submissions intended to upgrade studies. Additionally your submission of data .intended to
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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.
-"• ' : -. ' ' * '. ' i
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
generally wiJUi 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 hi 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. .
TV. CONSEQUENCES OF FAILURE TO COMPLY WITH THIS NOTICE
IV-A NOTICE OF INTENT TO SUSPEND
i .- • '• . • /...•' ' • » ..'''-• .. •'
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:
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1. Failure to respond as required by this Notice within 90 days of your receipt of this
Notice. '
/ - t
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.
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 ffl-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 hi 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 tune 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
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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 hi me 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
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 prptpcols, 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.
TJie 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 produces) only in exceptional
circumstances. If you believe such disposition of existing stocks of your product(s) which may be
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.
. -• •- " /' 85 '•' *'.-'.• .. : -'" •'-.-"••
-------
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 Rossi, Division Director
Special Review and
Reregistration Division
86
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Attachments
1 -
2 -
3 -
4 -
5 -
6 -
Data Call-in Chemical Status Sheet
Product-Specific Data Call-in Response Form
Requirements Status and Registrant's Response Form ,
EPA Batching of End-Use Products for Meeting Acute Toxicology Data
Requirements for Reregistration
List of Registrants Receiving This Notice
Cost Share and Data Compensation. Forms, and Confidential Statement of Formula
form .
87
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BRONOPOL DATA CALL-IN CHEMICAL STATUS SHEET
INTRODUCTION
You have been sent this Product Specific Data Call-In Notice because you have product(s)
containing bronopol.
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 bronopol.
.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 mis bronopol 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 Jhe database for bronopol are contained
in the Requirements Status and Registrant's Response, Attachment 3. The Agency has concluded
that additional data on bronopol 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 bronopol products.
INQUIRIES AND RESPONSES TO THIS NOTICE
If you have any questions regarding the generic database of bronopol, please contact Ron
Kendall at (703) 308-8068. If you have any questions regarding the product specific data
requirements and procedures established by this Notice, please contact Frank Rubis at (703) 308-
8184. ' ' ' •• '•''•'-.
All responses to this Notice for the Product Specific data requirements should be submitted
to:
Frank Rubis
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: bronopol
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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.
Item7a. 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.
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.
90
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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, hi 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 mrough
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?. 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 hi 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
91
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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 hi 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 aU 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
92
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completed and signed copies of the Confidential Statement of Formula (EPA Form
8570-4). ,
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
understandI that this option is available only for acute toxicity or certain efficacy cjata
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 MRID 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 thisNotice 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.
93
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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 guidelines 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, Subpart c. ,
Item 5. The study title associated with the guideline reference number is identified.
Item 6. The use patters (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 Documents unless EPA
determines that a longer tune 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.
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 on 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
committing to submit or provide the required data; if the required study is not
submitted on time, my product my be subject to suspension.
94
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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 mis 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 parry which is committing to submit or provide the require 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 hi the Data Call-In Notice (Section m-
C.l.) apply as well.
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 mat
I have determined that this study will fill the data requirement for which I have
indicated this choice.
5. By the specified due date, I will submit or cite data to upgrade a study
classified by the Agency as partially acceptable and upgrade (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.
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 MRID or Accession number (s) number (s) for
the cited data on a "Product Specific Data Report" form or in a similar format. If I
cite another registratrant's data, I will submit a completed "Certification With Respect
To Data Compensation Requirements" form.
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
• -". '; 95 : •. ' •- ' • •' .
-------
or provide information in support of my request. If the Agency approves my waiver
request, I will not be require 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 chosen. I also understand that the deadline for
submission of data as specified by the original data cal-in notice will not change.
Items 10-13. Self-explanatory. •,
NOTE:You may provide additional information that does not fit on this form in a signed letter
mat 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 cancelled this product. For
these cases, please supply all relevant details so that EPA can ensure that its records are correct.
96
-------
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EPA'S BATCHING OF 2-BROMO-2-NITROPROPANE-l,3-DIOL PRODUCTS FOR
MEETING REREGISTRATION ACUTE TOXICITY DATA REQUIREMENTS
In an effort to reduce the time, resources and number of animals needed to fulfill the
acute toxicity data requirements for reregistration of products containing 2-Bromq-2-
nitropropane-l,3-diol 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 compositio'n 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 registrant's 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 registrant chooses to
generate the data for a batch, he/she must use one of the products within the batch as the test
material. If a registrant chooses to rely upon previously submitted acute toxicity 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 not been significantly altered since submission and acceptance of the
acute toxicity data. Regardless of whether new data is generated or existing data is referenced,
registrants 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. x
In deciding how to meet me product specific data requirements, registrants must follow
the directions given in the Data Call-in Notice and its attachments appended to the RED. The
DCI Notice contains two response forms which are to be completed and submitted to the Agency
within 90 days of receipt. The first form, "Data Call-in Response," asks whether the registrant
will meet the data requirements for each product. The second form, "Requirements Status and
Registrant's Response," lists the product specific data required for each product, including the
standard six acute toxicity tests. A registrant who wishes to participate in a batch must decide
whether he/she will provide the data or depend on someone else to do so. If a registrant supplies
the data to support a batch of products, he/she must select one of the following options:
Developing Data (Option 1), Submitting an Existing Study (Option 4), Upgrading an Existing
Study (Option 5) or Citing an Existing Study (Option 6). If a registrant depends on another's
data, he/she must choose among: Cost Sharing (Option 2), Offers to Cost Share (Option 3) or
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
101
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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.
Twenty-one products were found which contain 2-Bromo-2-nitropropane-l,3-diol as an
active ingredient. The products have been placed into five batches and a "no batch" group in
accordance with the active and inert ingredients, type of formulation and current labeling. Table
1 identifies the products in each batch. Table 2 lists the products which have been placed in the
"no batch" category.
Table 1
Batch
1
2
3
• 4
5
EPA Reg. No.
33753-17
48301-35
33753-6
48301-29
33753-7
48301-28
3876-148
45017-40
5009-50
33753-1
33753-3
33753-5
33753-11
48301-18
48301-27
48301-36
67212-1
% 2-Bromo-2-nitropropane-l;3-
diol
10.0
10.0
18.2
18.2
40.8
40.8
9.5
Dodecylguanidine Hydro-chloride
4.7
~' 9.5
Dodecylguanidine Hydro-chloride
4.7
95.0
99.0
95.0
95.0
97.0.
95.0 .
95.0
97.0
95.0
•
Formulation Type
*£, * !•>
Liq
Liq
Liq
Liq
Liq
Liq
Liq
Liq
Solid
Solid
Solid
Solid
Solid
Solid
Solid
Solid
Solid
102
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The following table lists products that were either considered not to be similar or the
Agency lacked sufficient information for decision making and were not placed in any batch. The
registrants of these producs are responsible for meeting the acute toxicity data requirements
separately.
Table 2 (No Batch)
"" , EPA Reg,'. No? X
I > ! *"' , , <
3876-147
33752-13
33753-18
48301-25
-,s , ',, % active ingredient, ' .--
2-Bromo-2-nitropropane -
l,3-dio!5.3
N-alkyl dimethylbenzyl ammonium chloriode
10.0
2-Bromo-2-nitropropane -
s l,3-diol55,0
2-Bromo-2-nitropropane -
l,3-dio!81.2
2-Bromo-2-nitropropane -
l,3-dio!38.0
„ Fopnulation Type
Liq
Solid
Solid
SoUd
103
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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.
d.
e.
f.
g.
h.
i.
j-
k.
.1.
m.
n.
The CSF must be signed, dated and the telephone number of the responsible party
must be provided.
All applicable information which is on the product specific data submission must
also be reported on the CSF.
All weights reported under item 7 must be in pounds per gallon for liquids and
pounds per cubic feet for solids.
t / ' - •.'- .--.'' ', ; - .
Flashpoint must be in degrees Fahrenheit and flame extension in inches.
For all active ingredients, the EPA Registration Numbers for the currently
registered source products must be reported under column 12.
The Chemical Abstracts Service (CAS) Numbers for all actives and inerts and all
common names for the trade names must be reported.
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.
All the weights in columns 13.a. and I3.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).
All the items under column 13.b. must total 100 percent.
All items under columns 14.a. and 14.b. for the active ingredients must represent
pure active form.
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.
When new CSFs are submitted and approved, all previously submitted CSFs
become obsolete for that specific formulation.
105
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108
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SEPA
United States Environmental Protection Agency
Washington, DC 20460
CERTIFICATION QF OFFER TO COST
SHARE IN THE DEVELOPMENT OF DATA
Form Approved
OMB No. 2070-0106
2070-0057
Approval Expire* 3-31-%
Public reporting burden for this collection of information 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 theOffice
of Management and Budget, Paperwork Reduction Project (2070-0106), Washington, DC 20503. .
-•'''. . ' -v
Please fill in blanks below. •
Company Name
Company Number'
Product Name
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 Rodenticlde 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): •
Him* of Flrm(»)
Oil* of Off*r
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 applfcabte law.
Signature of Company** Authorized Rapr«*tnutlv«
Dal*
Nam* and Till* (Pl«a»« Type or Print)
EPA Form 8570J2 (5/91) Hepluon EPA form 8580. which is obsolete
109
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110
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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
•lie reporting burden for this collection of information is estimated to average 1 &minutes per response, including time for
ewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing the
ection of information. Send comments regarding the burden estimate or any other aspect of this collection of information,
uding suggestions for reducing this burden to, Chief Information Policy Branch, PM-233, U.S. Environmental Protection
sncy, 401 M St., S.W., Washington, DC 20460; and to the Office of Management and Budget, Paperwork Reduction Project
70-0106), Washington, DC 20503.
ase fill in blanks below. . :
ipany Name • ,
/ • -
luctName ' •
Company Number
EPA Reg. No.
rtifythat:
t " ' . " • ,",'•
For each study cited in support of registration or reregistratiion under the Federal Insecticide, Fungicide and Roderiticide Act
:RA) that is an exclusive use study, I am the original data submitter, or I have obtained the written permission of the original
»submitter to cite that study. ,
That for each study cited in support of registration or reregistration under FIFRA that is NOT an exclusive use study, I am the
inal data submitter, or I have obtained the written permission of the original data submitter, or I have notified in writing the
ipany(ies) that submitted data I have cited and have offered to: (a) Pay compensation.for those data in accordance with sections
(1 )(F) and 3(c)(2)(D) of FIFRA; and (b) Commence negotiation to determine which data are subject to the compensation
lirement of FIFRA and the amount of compensation due, if any. The companies I have notified are. (check one)
The companies who have submitted the studies listed on the back of this form or attached sheets, or indicated on the attached
quirements Status and Registrants'Response Form,"
That Ihave previously complied with section 3(c)(1)(F) of FIFRA for the studies I have cited in support of registration or
gistration under FIFRA.
ature ' • •'..;••'.•'
Date
and Title (Please Type or Print)
MERAL OFFER TO P.AY: I hereby offer and agree to pay compensation to other persons, with regard to the registration or
jgistration of my products, to the extent required by FIFRA section 3(c)(1)(F) and 3(c)(2)(D).
ature
Date
le and Title (Please Type or Print)
rm 8570-31 (4-96)
111
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112
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The following is a list of available documents related to bronopol. It's purpose is to
provide a path to more detailed information if it is needed. These accompanying documents
are part of the Administrative Record for bronopol and are included in the EPA's Office of
Pesticide Programs Public Docket.
1. Health and Environmental Effects Science Chapters
2, Detailed Label Usage Information System (LUIS) Report
3. bronopol RED Fact Sheet
4. PR Notice 86-5 (included in this appendix)
5. PR Notice 91-2 (included in this appendix) pertains to the Label Ingredient
Statement
113
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