United States Chemical Safety December 2011 Environmental Protection and Pollution Prevention Agency (7510P)



# Bronopol Registration Review : Final Work Plan December 2011Docket Number: EPA

- HQ

- OPP

- 2011

- 0421 www.regulations.gov

3 of 14 Bronopol Registration Review Team

William Hazel Human Health & Environmental Effects

Srinivas Gowda

Eliza Blair Risk Management

Lance Wormell

Philip Ross Office of General Counsel

________________________________________ S upporting documents for the Bronopol Case may be found in the registration review docket EPA

- HQ

- OPP

- 2011

- 0421 located on the internet at www.regulations.gov

.Docket Number: EPA

- HQ

- OPP

- 2011

- 0421 www.regulations.gov

4 of 14 This is the Final Work Plan (FWP) of the Environmental Protection Agency (EPA o r “the Agency”) for the registration review of bronopol (Case 2770 )

. The work plan includes the expected registration review timeline . The work plan also addresses public comments received concerning the Preliminary Work Plan (PWP) in the Summary Document which was posted in the bronopol registration review docket , and any other comments concerning the initial docket postings. The Summary Document provided information on what EPA knows about the pesticide and what additional risk analyses and data or information the Agency believes are needed to make a registration review decision. Introduction

The Agency is implementing the registration review program pursuant to Section 3(g) of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and will review each registered pesticide every 15 years to determine whether it continues to meet the FIFRA standard for registration. Changes in science, public policy and pesticide use practices will occur over time. The registration review program is intended to make sure that, as the ability to assess risk evolves and as policies and practices change, all registered pesticides continue to meet that statutory standard. The public phase of registration review begins when the initial docket is opened for each case. Informatio n on this program is provided at: http://www.epa.gov/oppsrrd1/registration_review/.

The Bronopol Preliminary Work Plan (PWP) (PC Code 216400 ) was published on June 29, 2011 and the 6 0

- day comment period ended on August 29, 2011 . The Preliminary Work Plan document is available on www.regulations.gov docket number EPA

- HQ

- OPP

- 2011

- 0421

. The first product containing 2

- Bromo

- 2

- nitro

- 1,3

- propanediol ( Bronopol ) (PC Code 216400 ) as an active ingr edient was registered in the United States in 1984

. Currently, there are 42 products registered with EPA. Bronopol is a bacteriostat, fungicide, microbicide, microbiostat, antimicrobial, and algaecide contained in products registered for use as a materials preservative, in industrial process water systems, and in HVAC systems. Products containing bronopol are also registered for use to preserve adhesives, metalworking fluids, absorbent clay, starch slurries, pigment slurries, mineral slurries, paints, emul sion systems, water

- based printing inks and fountain solutions, paper, and bulk pulp. The following water systems may be treated: paper mill process water systems, recirculating water cooling towers, evaporative condensers, air scrubber systems, air cond itioning systems, humidifying systems, and o il and gas drilling fluids

. In HVAC systems
, the following may be treated: furnaces, air handlers, coils, fans, fan housings, sheet metal ducts, air supply and return ducts, humidifiers, dehumidifiers, and air intake and discharge devices. Bronopol has been widely used for decades as a preservative in pharmaceuticals, cosmetics, and other personal care products regulated by the Food & Drug Administration (FDA). Bronopol is exempt from the requirement of a tolerance when used at ≤400 ppm as an inert ingredient in conventional pesticide products used on crops and animals. Bronopol is approved by the FDA for indirect food contact under 21 CFR 175.105 (c)(5), 21 CFR 176.170 (a)(5), 21 CFR 176.180 (b)(1), 21 CFR 176.300. A RED was completed for bronopol in 1995.Docket Number: EPA

- HQ

- OPP

- 2011

- 0421 www.regulations.gov

5 of 14 The Agency received comments from one registrant during the public comment period on the initial docket, described below. In the PWP, the Agency solicited comments on specifi c topics: environmental justice, water body impairment
, trade irritants , and structure activity relationships

. No comments or information were received during the public comment period concerning these issues. Comments Received on the Preliminary Work Plan

Comment: The Agency indicated in its Summary Document that bronopol is not approved for any kind of food

- contact use. In fa ct, bronopol is approved by the FDA for indirect food contact under the following: 21 CFR 175.105 (c)(5), 21 CFR 176.170 (a)(5), 21 CFR 176.180 (b)(1), 21 CFR 176.300.

Response: The Agency thanks the registrant for this correction. Future documents
, includ ing this Final Work Plan
, will include th at correct ed information.

Comment: The registrant has in the past submitted a study (MRID 47256605) that may satisfy the data requirement 835.3110

- Ready Biodegradability.

Response: The Agency will review this st udy as part of its risk assessment for bronopol and encourages the registrant to cite this study when responding to the data call

- in (DCI) anticipated to be issued for this case

.
Comment: Although it is not listed in the anticipated data requirements table, the Summary Document suggests that bystander formaldehyde exposure data will be required. Bystander exposure data are not applicable for industrial use sites.

Response:

The comments received during the initial public comment period did not affect t he data needs, work plan and timeline described in the PWP ; however, the Agency expects to require two additional ecological studies that were not included in the anticipated the data needs section of the PWP

. These additional studies that the Agency anti cipates requiring are “835.3220

-- Porous Pot Test ” and “835.3240

-- Simulation Test

- Aerobic Sewage Treatment: A. Activated Sludge Units ” . They were not included in the PWP because they were not required for down

- the

- drain exposure assessment at that ti me, and are being added to the FWP because they are now part of the standard suite of studies that the Agency anticipates needing to assess down

- the

- drain exposure

. The referenced p hrase on page 15 of the Summary Document was "postapplication/bystander formaldehyde exposure". The Agency still anticipates needing postapplication formaldehyde exposure data.

This document makes final the work plan for the bronopol registration review process.

The Agency will conduct a comprehensive ecological risk assessment, including an endangered species risk assessment, for all uses of bronopol

. The Agency will conduct a human health risk Risk Assessments and Anticipated Data NeedsDocket Number: EPA

- HQ

- OPP

- 2011

- 0421 www.regulations.gov

6 of 14 assessment. The Agency anticipates the need to require additional data for use in conducting the registration review for bronopol

.
EPA believes that bronopol releases formaldehyde (HCHO) under certain conditions; therefore, this Registration Review also addresses potential ris ks associated with formaldehyde exposure from bronopol use. Products containing formaldehyde as an active ingredient will be evaluated under registration review Case 0556. EPA’s formaldehyde RED is available in the formaldehyde public docket at http://www. regulations.gov in docket number EPA

- HQ

- OPP

- 2008

- 0121.

Ecological Risk Assessment Status and Data Needs

**•** The most recent ecological risk assessment for bronopol was performed in 1995 in support of the bronopol RED

.

**•** The Agency anticipates the need to require the following additional ecological data for use in conducting the registration review of bronopol

.
850.1300

-- Daphnid chronic toxicity test 850.1400

-- Fish early

- life stage toxicity test (freshwater) 850.4225

-- Seedling emergence, Tier II

- dose response study on rice (Oryza sativa); 850.4250

-- Vegetative vigor, Tier II

- dose response study on rice (Oryza sativa); 850.4400

-- Aquatic plant growth (aquatic vascular plant toxicity), Tier II

- using Lemna gibba , Tier I 850.5400

-- Aquatic plant growth (algal toxicity), Tier II

- dose response studies on four species

**•** The Agency anticipates the need to require the following additional environmental fate data for use in conducting the registration review of bronop ol

.
850.6800

-- Modified activated slud ge respiration inhibition test 835.3110

-- Ready biodegradability 1 835.3220

-- Porous Pot Test 1 835.3280

-- Simulation Tests to Assess the Biodegradability of Chemicals Discharged to Wastewater 1 835.3240

-- Simulatio n Test

- Aerobic Sewage Treatment: A. Activated Sludge Units 1

1 The results of the Activated Sludge Respiration Inhibition Test (ASRI) expected to be required will determine which of these three biodegradation tests would be anticipated to be required. If the ASRI test EC 50 is less than or equal to 20 mg/L, then either the Biodegradation in Activated Sludge Study or Simulation Test

– Aerobic Sewage Treatment: A. Activated Sludge Units or the Porous Pot Test would be antici pated to be required. If the ASRI test EC 50 is greater than 20 mg/L, then the applicant would choose to conduct either: (i) Ready Biodegradability or (ii) Biodegradation in Activated Sludge or Simulation Test

– Aerobic Sewage Treatment: A. Activated Sludg e Units or the Porous Pot Test. If the antimicrobial passes the ready biodegradability study, then no further testing would be expected to be required. If, however, the antimicrobial fails the ready biodegradability study, then the Biodegradation in Acti vated Sludge or Simulation Test

– Aerobic Sewage Treatment: A. Activated Sludge Units, or the Porous Pot study would be expected to be required.Docket Number: EPA

- HQ

- OPP

- 2011

- 0421 www.regulations.gov

7 of 14 **•** F or more information
, please refer to Summary of Product Chemistry, Environmental Fate, and Ecotoxicity Data for the Bronopol Registration Review Decision Document , located in the docket

.
Human Health Risk Assessment Status and Data Needs

**•** The most recent human health risk assessment for bronopol was performed in 1995 in support of the bronopol RED

.

**•** Dietary (food) exposure could potentially occur because bronopol is used as an in

- can preservative or preservative during storage or use of materials including the following: bulk paper pulp, paper and paperboard water systems, water

- based coatings, dishwashing liquids, and premoistened sponges and wipes. Residue transfer fro m these preserved materials to food may occur. The labels do not preclude food contact use of these materials. A dietary exposure and risk assessment addressing use of bronopol as an active ingredient has not been conducted in the past. However, a dieta ry (food source) risk assessment is now expected to be necessary. Dietary Assessment

**•** A drinking water assessment has not been conducted for bronopol in the past. However, a number of the industries making use of bronopol periodically discharge waste water. Although the ext ent to which bronopol will survive waste water treatment is not known, it is fairly likely that bronopol could contaminate surface or ground water, and hence drinking water as a result of antimicrobial use patterns. Based on the present use scenarios on t he bronopol labels, a drinking water assessment is warranted at this time.

**•** Bronopol is exempt from the requirement of a tolerance when used at ≤400 ppm as an inert ingredient in conventional pesticide products used on crops and animals. Additionally, bronopol is approved by the FDA for indirect food contact under 21 CFR 175.105 (c)(5), 21 CFR 176.170 (a)(5), 21 CFR 176.180 (b)(1), and 21 CFR 176.300. Tolerances and International Harmonization

**•** The most recent occupational and residential exposure assessment was performed in support of the bronopol RED in 1995. Occupational and Residential Assessment and Risk

**•** Assessments of occupational risk are planned for this registration review because bronopol products are added to preserve industrial mate rials during the manufacturing process using open

- pour or metered pump application methods which may result in dermal and inhalation exposure to workers.

**•** Bronopol hydrolyzes to release formaldehyde which may result in worker inhalation
exposure. Because the conditions under which bronopol releases formaldehyde and the rate of release are unknown, p ostapplication formaldehyde exposure data are anticipated to beDocket Number: EPA

- HQ

- OPP

- 2011

- 0421 www.regulations.gov

8 of 14 needed to assess inhalation risks posed to workers in pulp and paper mills, machine shops, and other industrial facilities ma nufacturing preserved materials. In addition to the data expected to be required through registration review, a small chamber study could be substituted for the indoor inhalation exposure data the Agency anticipates needing. T he Agency encourages registrants who wish to conduct a s mall chamber study in place of indoor inhalation exposure to discuss a protocol with the Agency. A small chamber study would allow the Agency to better estimate the ma gnitude of occupational (mixer/l o ader) formaldehyde inhalation exposure while using bronopol products as preserving materials in the manufacturing facility, using treated metalworking fluids, using products containing bronopol in paper and paperboard mill water systems, painting with pres erved paint, and applying preserved coatings.

**•** Assessments of residential risk are planned for registration review because materials preserved with Bronopol are intended for residential, commercial, and institutional use and may result in exposure of the general public and homeowners to the parent compound and formaldehyde . Such materials include latex paints, resin/latex/polymer emulsions, or det ergent and polish suspensions. T o help the Agency determine whether or not residential or other nonoccupational exposure to the parent compound or formaldehyde is likely to occur from its use as a preservative, the Agency encourages registrants to submit detailed information on physical and chemical properties and use information to elucidate the conditions, rates, and magnitude of formaldehyde release from Bronopol under various conditions and in various materials.

**•** The Agency has not conducted an aggregate risk assessment for bronopol. Aggregate and Cumulative Exposure and Risk

**•** In examining aggregate exposure, EPA takes into account the available and reliable information concerning exposures to pesticide residues in food and drinking water, as well

as non

- occupational pesticide exposures. Assessments of aggregate risk are planne d for registration review because dietary (food) and residential painter/postapplication exposures are expected to occur. In addition, bronopol residues may also reach drinking water as a result of industrial discharges. However, the potential need to incl ude drinking water exposure in the aggregate assessment will be revisited upon receipt of the additional environmental fate data anticipated to be required through registration review

. The specifics of necessary aggregate assessments will be determined dur ing the risk assessment stage of this

r egistration r eview.

**•** EPA does not have, at this time, available data to determine whether Bronopol has a common mechanism of toxicity with other substances or how to include this pesticide in a cumulative risk assessment. For the purposes of this Registration Review, EPA has assumed that Bronopol does not have a common mechanism of toxicity with other substances when used as an antimicrobial as registered.

Human Health Data NeedsDocket Number: EPA

- HQ

- OPP

- 2011

- 0421 www.regulations.gov

9 of 14 **•** The Agency anticipates the need to require the following additional human health data for use in conducting the registration review of Bronopol

.
870.3465

-- 90

- day inhalation toxicity (rat) 875.1700

-- Product use information (outdoor) 875.2700

-- Product use information (indoor) 875.2800

-- Description of human activity 875.1100

-- Dermal outdoor exposure 875.1200

-- Dermal indoor exposure 875.1300

-- Inhalation outdoor exposure (HRSB costs not included) 875.1400

-- Inhalation indoor exposure * 875.1600

-- Application exposure data reporting and calculations 875.2900

-- Data reporting and calculations

* The antici pated DCI will provide that the indoor inhalation exposure a nticipated data requirement may also be met with a small chamber study to determine the level of human exposure to formaldehyde in residential and occupational settings. The anticipated DCI will provide that r egistrants seeking to conduct a small chamber s tudy must discuss a protocol with the Agency to ensure that the study will meet EPA guidelines.

**•** For more information, please refer to 2

- Bromo

- 2

- nitropropane

- 1,3

- diol. Human Health Effects Scoping Document for the Registration Review Decision
, located in the docket

. Product Chemistry Data Needs

**•** The Agency does not anticipate the need to require additional product chemistry data for the registration review at this time.

**•** F or more information
, please refer to Summary of Product Chemistry, Environ mental Fate, and Ecotoxicity Data for the Bronopol Registration Review Decision Document
, located in the docket

.

Ecological: Incidents:

**•** No Bronopol ecological incidents have been reported in Agency's Ecological Incident Information System (EIIS)

.

Human Hea lth:

**•** Four human poisoning incidents have been confirmed as being due to Bronopol exposure. These are summarized as follows:

1. A residential use of a bronopol product to treat HVAC ducts resulted in the homeowner becoming sick. No more detailed information was provided. 2. A worker was splashed on the upper arm with approximately 2 ml of a 25% solution of bronopol in water. The worker promptly washed the area wit h soap and water. TheDocket Number: EPA

- HQ

- OPP

- 2011

- 0421 www.regulations.gov

10 of 14 worker experienced no immediate pain. The exposed area began to itch later that evening and then blister. The worker went to a doctor who said it was a second degree burn. 3. A worker who uses a printing press claims that (s)he has deve loped a chemical allergy to bronopol. 4. A man reported that he was sick after the HVAC system in his house was treated with a bronopol product. The person began having some adverse reactions to the chemical treatment immediately after re

- entering the house. The reactions became more intense until he finally had to leave the house.

Endangered Species

**•** The Agency has not conducted a risk assessment that supports a complete endangered species determination for Bronopol

. The ecological risk assessment planned during registration review will allow the Agency to determine whether Bronopol ’s use has 'no effect' or 'may affect' federally listed threatened or endangered species (listed species) or their designated critical habitats. When an assessment concludes that a pesticide’s use 'may affect' a listed species or its designated critical habitat, the Agency will consult with the U.S. Fish and Wi ldlife Service and/or National Marine Fisheries Services (the Services), as appropriate.

Endocrine Disruptor Screening Program
As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Col lectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to end ocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates a cute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its reregistration d ecision for bronopol , EPA reviewed these data and selected the most sensitive endpoints for relevant ris k assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), Bronopol is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whethe r certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormona l systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary base d on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and establish a dose

- response relationship between the dose and the E, A, or T effect.Docket Number: EPA

- HQ

- OPP

- 2011

- 0421 www.regulations.gov

11 of 14 Under FFDCA section 408(p), the Agency mus t screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. Bronopol is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Accordingly, as part of registration review, EPA will issue future EDSP orders/data call

- ins, requiring the submission of EDSP screening assays for Bronopol

. For further inf ormation on the status of the EDSP, the policies and procedures, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/

.Docket Number: EPA

- HQ

- OPP

- 2011

- 0421 www.regulations.gov

12 of 14 Timeline

EPA has created the following es timated timeline for the completion of the Bronopol registration review:

Anticipated Schedule Activities Estimated Month/Year Phase 1: Opening the docket Open Public Comment Period for Docket Completed June 2011 Close Public Comment Period for Docket Completed August 2011 Phase 2: Case Development Develop Final Work Plan (FWP) Completed December 2011 Issue DCI December 2012 Data Submission December 2014 Open Public Comment Period for Preliminary Risk Assessments June 2016
Close Public Comment Period for Preliminary Risk Assessments July 2016 Phase 3: Registration Review Decision Open Public Comment Period for Proposed Reg. Review Decision December 2016 Close Public Comment Period for Proposed Reg. Review Decision February 2017 Final Decision and Begin Post

- Decision Follow

- up June 2017 Total (years) 6

Next Steps

A DCI will be developed regarding the data needs listed under the “Risk Assessments and Anticipated Data Needs” section of this document. The Agency expects to issue the DCI in December 2012 . Human health and environmental fate and ecological hazard assessments will be conducted for all uses.Docket Number: EPA

- HQ

- OPP

- 2011

- 0421 www.regulations.gov

13 of 14 Summary of Anticipated Data Requirements

– Bronopol

The table below summarizes anticipated data needs for the registration review of bronopol.

Table 1. Summary of Anticipated Data Requirements

– Bronopol

Guideline Number Anticipated Data Requirement Test Material Estimated Timeframe (Measured in months from DCI Receipt)

835.3110 Ready biodegradability i TGAI 12

835.3220 Porous Pot Test i 2 TGAI 12

835.3280 Simulation Tests to Assess the Biodegradability of Chemicals Discharged to Wastewater i TGAI 12

835.3240 Simulation Test

– Aerobic Sewage Treatment: A. Activated Sludge Units i 2 TGAI 12

850.1300 Aquatic invertebrate life

- cycle, freshwater species TGAI 24

850.1400 Fish early

- life stage toxicity test, freshwater species TGAI 24

850.4225 Seedling emergence, Tier II

- dose response study on rice (Oryza sativa) TGAI 24

850.4250 Vegetative vigor, Tier II

- dose response study on rice (Oryza sativa) TGAI 24

850.4400 Aquatic plant toxicity test, vascular species TGAI 24

850.5400 Aquatic plant toxicity test, non

- vascular (4 species) TGAI 12

850.6800 Modified Activated Sludge Respiration Inhibition TGAI 24

870.3465 90

- day inhalation toxicity (rat) TGAI 48

875.1100 Dermal outdoor exposure TGAI 24

875.1200 Dermal indoor exposure TGAI 24

875.1300 Inhalation outdoor exposure TGAI 24

875.1400 Inhalation indoor exposure ii TGAI 24

2 These two studies were not listed as anticipated data needs in the Bronopol Preliminary Work Plan; they are new additions to the standard suite of down

- the

- drain data that the Agency anticipates needing for risk assessment.Docket Number: EPA

- HQ

- OPP

- 2011

- 0421 www.regulations.gov

14 of 14 875.1600 Application exposure data reporting and calculations TGAI 24

875.1700 Product use information (outdoor) TGAI 24

875.2700 Product use information (indoor) TGAI 24

875.2800 Description of human activity TGAI 24

875.2900 Data reporting and calculations TGAI 24

i The results of the Activated Sludge Respiration Inhibition Test (ASRI) expected to be required will d etermine which of these three biodegradation tests would be anticipated to be required. If the ASRI test EC 50 is less than or equal to 20 mg/L, then either the Biodegradation in Activated Sludge Study or Simulation Test

– Aerobic Sewage Treatment: A. Acti vated Sludge Units or the Porous Pot Test would be anticipated to be required. If the ASRI test EC 50 is greater than 20 mg/L, then the applicant would choose to conduct either: (i) Ready Biodegradability or (ii) Biodegradation in Activated Sludge or Simul ation Test

– Aerobic Sewage Treatment: A. Activated Sludge Units or the Porous Pot Test. If the antimicrobial passes the ready biodegradability study, then no further testing would be expected to be required. If, however, the antimicrobial fails the read y biodegradability study, then the Biodegradation in Activated Sludge or Simulation Test

– Aerobic Sewage Treatment: A. Activated Sludge Units, or the Porous Pot study would be expected to be required.

ii The indoor inhalation exposure data requirement ma y also be met with a small chamber study to determine the level of human exposure to formaldehyde in residential and occupational settings. Registrants seeking to conduct a small chamber study must discuss a protocol with the Agency to ensure that the stud y will meet EPA guidelines

.