Docket Number; EPA-HQ-OPP-2010-0693

www.regulations.gov

1

United States Chemical Safety June 2011

Environmental Protection and Pollution Prevention

Agency (7510P)

Calcium Oxide

Registration Review: 

Final Work Plan

June 2011
Docket Number; EPA-HQ-OPP-201 0-0693 

www.regulations.gov 

Calcium Oxide 

Registration Review: 

Final Work Plan 

June 2011 

Case # 5104 

Approved By: 

~ Harrigan

~~-Farrelly l Director, Antimicrobials Division 

Date: 

I I 

2 
Docket Number; EPA-HQ-OPP-2010-0693

www.regulations.gov

3

Calcium Oxide Registration Review Team

Michelle Centra

Human Health & Environmental Effects

Najm Shamim

Rebecca von dem Hagen

Risk Management

Lance Wormell

Philip Ross

Office of General Counsel

________________________________________

Supporting documents for the Calcium Oxide Case may be found in the registration review 

docket EPA-HQ-OPP-2010-0693 located on the internet at www.regulations.gov.
Docket Number; EPA-HQ-OPP-2010-0693

www.regulations.gov

4

This is the Final Work Plan (FWP) of the Environmental Protection Agency (EPA or “the 

Agency”) for the registration review of the Calcium Oxide Case (Case 5104). 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 Calcium Oxide Case 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. Information on this program is provided at: http: 

//www.epa.gov/oppsrrd1/registration_review/.

Calcium oxide (PC Code 075601) is a bacteriocide/bacteriostat contained in a product registered 

for use in the treatment of medical waste. Calcium hydroxide (PC Code 075604), created by the 

mixing of calcium oxide and water, is a bacteriocide/bacteriostat contained in a manufacturing 

use product (MUP) registered for use for the manufacture of or fabrication into antimicrobial 

products to be used as coatings on or components of the following hard, inanimate surfaces and 

products: walls, floors, ceilings, tile, fixtures, tools, appliance exteriors, pipe exteriors, heating 

cooling ventilation (HVAC) equipment, duct work and related equipment (other than motors, 

fans and similar mechanical moving parts) interiors and exteriors, and concrete, stone, ceramic, 

plaster, wood, drywall substrates in residential dwellings, schools, day care centers, professional 

offices, commercial and industrial buildings, factories, animal housing facilities (barns, corrals, 

fences) and healthcare facilities (hospitals, medical office, nursing homes). 

Both calcium oxide and calcium hydroxide were new active ingredients in products registered in 

1976. In 1989 all of the registered products containing calcium oxide or calcium hydroxide were 

voluntarily cancelled; therefore, these active ingredients were not evaluated under reregistration. 

In 2002 and 2004 EPA registered new products containing calcium oxide and calcium hydroxide, 

respectively.

The Calcium Oxide Preliminary Work Plan (PWP) was published on December 22, 2010 and the 

60-day comment period ended on February 22, 2011. The Preliminary Work Plan is available on 

www.regulations.gov docket number EPA-HQ-OPP-2010-0693.
Docket Number; EPA-HQ-OPP-2010-0693

www.regulations.gov

5

Comments Received on the Preliminary Work Plan

The Agency received one comment from the Physicians Committee for Responsible Medicine 

(PCRM) during the public comment period on the initial docket, described below. In the PWP, 

the Agency solicited comments on specific topics: environmental justice, water body 

impairment, trade irritants, and structure activity relationships. One comment, described below,

was received during the public comment period concerning structure activity relationships.

Comment: PCRM encourages the registrant to use existing information and (Q)SAR to 

determine if an acute threshold or “limit test” approach can be used to fulfill data 

requirement 850.1075 Acute Fish Toxicity Study. If this approach is determined to be 

appropriate and utilized, it will reduce the number of animals used.

Response: As stated on page 11 of the calcium oxide summary document (available at 

regulations.gov in docket ID EPA-HQ-OPP-2010-0693) , “If stakeholders believe that 

submission of predicted data can fulfill one of the data needs for the calcium oxide case, 

then the Agency invites submission of this information. The submitter would be 

expected to supply a rationale describing the utility of the information and provide 

documentation on the scientific validity of the information. The determination that the 

predicted data fulfills the data requirement would be at the sole discretion of the Agency. 

Pre-submission consultation with the Agency is encouraged.”

The Agency has considered and will continue to consider possible acceptance of 

SAR/(Q)SAR information/data to fulfill its data requirements on a case-by-case basis. 

The Agency supports a tiered testing framework for data requirements, providing for 

greater efficiency of testing resources while assuring data development as warranted for 

an assessment. As part of this scheme all available information, including use patterns, 

exposure, existing toxicity and SAR/(Q)SAR information if applicable, should be used to 

inform the decision as to where within the tiered framework testing should be initiated 

and to inform the test design when testing is required. The Agency will consider a tiered 

testing framework based on the information and the supporting rationale submitted by the 

registrant. 

Comment: PCRM believes that because calcium oxide compounds are known to be 

severely corrosive, the 28-day inhalation toxicity (870.3465) and 21/28-day dermal 

toxicity (870.3200) studies should not be required. In addition, PCRM argues that these 

studies cannot be diluted because that would not be the article and the technical grade 

(TGAI) is not a diluted substance as the final product is.

Response: The Agency does not require the undiluted TGAI be used to conduct the 28-

day inhalation toxicity (870.3465) and 21/28-day dermal toxicity (870.3200) studies. 

According to EPA’s published OPPTS Health Effects Test Guidelines 870.3465 and 

870.3200, “it is desirable to have a concentration-response relationship as well as a 

NOEL.... Therefore, at least three concentration levels plus a control and, where 

appropriate, a vehicle...shall be used. Doses should be spaced appropriately to produce 

test groups with a range of toxic effects.” The Agency anticipates submission of 

subchronic dermal and inhalation toxicity studies conducted with dilute concentrations of 
Docket Number; EPA-HQ-OPP-2010-0693

www.regulations.gov

6

either calcium oxide or calcium hydroxide that demonstrate toxic effects at noncorrosive/non-caustic levels. 

For use in conducting a complete human health/exposure risk assessment for all 

registered pesticide uses of the calcium oxide chemicals and to ensure that these 

chemicals meet the safety standards established by FFDCA, as amended by FQPA, the 

Agency anticipates requiring repeated dose dermal and inhalation toxicity studies as 

outlined in the PWP. 

The comments received during the initial public comment period did not affect the anticipated 

data needs, work plan and timeline described in the PWP and they remain as they were presented 

initially in the PWP. Further, this document makes final the work plan for the Calcium Oxide

Case registration review.

Risk Assessments and Anticipated Data Needs

• The Agency will conduct a comprehensive ecological risk assessment, including an 

endangered species risk assessment, for all uses of calcium oxide and calcium hydroxide.

The Agency also anticipates the need to conduct human health risk assessments for the 

calcium oxide case including an occupational risk assessment for calcium oxide and 

occupational and residential risk assessments for calcium hydroxide. The Agency expects to 

require additional data for use in conducting the registration review of the calcium oxide 

case.

Ecological Risk Assessment Status and Data Needs

• No ecological risk assessment has been performed for the calcium oxide case. 

• The Agency does not anticipate the need to complete an environmental fate risk assessment. 

Based on current use patterns no long term environmental impact is expected from calcium 

oxide or calcium hydroxide because once calcium enters the environment, it is expected to 

quickly reach background levels. No environmental fate data gaps exist for the present uses 

of these chemicals.

• The Agency anticipates the need to require the following additional ecotoxicity data for use 

in conducting an ecological risk assessment for the registration review of calcium oxide and 

calcium hydroxide.

o GDLN 850.1075 – Acute Freshwater Fish Toxicity 

o GDLN 850.5400 – Aquatic Growth, Tier II Green Algae 

• For more information, please refer to Preliminary Plan for Registration Review of: Calcium 

Hydroxide/Calcium Oxide, located in the docket.

Human Health Risk Assessment Status and Data Needs

• No human health risk assessment has been performed for the calcium oxide case. 
Docket Number; EPA-HQ-OPP-2010-0693

www.regulations.gov

7

Dietary Assessment

• Dietary (food and water) exposure is not expected from the registered use of calcium oxide 

because the chemical is applied in a closed system and must be disposed of in a sanitary 

landfill. Dietary exposure (food and water) is not expected from the registered calcium 

hydroxide manufacturing use product because it is not for use in or on coating or other 

antimicrobial pesticides that will be used on food contact, food preparation or food 

processing surfaces. The U.S. Food and Drug Administration considers calcium oxide and 

calcium hydroxide Generally Recognized as Safe (GRAS) for use in foods with no 

limitations except good manufacturing practices. Therefore, because non-occupational 

exposure and hazard are expected to be minimal, the Agency does not anticipate conducting 

dietary or aggregate risk assessments for the calcium oxide case.

Tolerances and International Harmonization

• Calcium hydroxide is exempt from the requirement of a tolerance when used as an inert 

ingredient as a solid diluent or carrier in pesticide formulations applied to growing crops or 

to raw agricultural commodities (40 CFR 180.1001(c)).

Occupational and Residential Assessment and Risk

• The Agency anticipates conducting an occupational risk assessment for calcium oxide and 

occupational and residential risk assessments for calcium hydroxide based on current use 

patterns. 

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. An aggregate risk assessment has not been deemed 

necessary for the calcium oxide case because non-occupational exposure and hazard are 

expected to be minimal. 

• EPA does not have, at this time, available data to determine whether calcium oxide and 

calcium hydroxide have 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 calcium oxide and 

calcium hydroxide do not have a common mechanism of toxicity with other substances when 

used as an antimicrobial as registered. 

Human Health Data Needs

• The Agency intends to reevaluate the existing submitted, cited and published data and 

evaluate anticipated toxicology data for calcium oxide and calcium hydroxide during the 

registration review risk assessment in order to better characterize hazard and potential human 

health risks. 
Docket Number; EPA-HQ-OPP-2010-0693

www.regulations.gov

8

• The Agency anticipates the need to require the following additional human health data for 

use in conducting the registration review of the calcium oxide case. 

Toxicology Data for Calcium Hydroxide or Calcium Oxide

o 870.3200 21/28-day Dermal Toxicity

o 870.3465 28-day Inhalation Toxicity

o 870.5100 Bacterial Reverse Mutation Test

o 870.5300 In vitro Mammalian Cell Gene Mutation Test or 870.5375 In vitro

Mammalian Chromosome Aberration Test

o 870.5385 Mammalian Bone Marrow Chromosomal Aberration Test or 870.5395 

Mammalian Erythrocyte Micronucleus Test

Exposure Data for Calcium Oxide (Occupational Applicator – Medical Waste; Loading; 

Open Pour)

o 875.1300 Inhalation Exposure- Outdoor

o 875.1400 Inhalation Exposure- Indoor

o 875.1600 Data Reporting and Calculations

o 875.1700 Product Use Information

Exposure Data for Calcium Hydroxide (Occupational/Residential Applicator –

Paints/Coatings; Brush, Roller, Spray-on)

o 875.1100 Dermal Exposure- Outdoor

o 875.1200 Dermal Exposure- Indoor

o 875.1300 Inhalation Exposure- Outdoor

o 875.1400 Inhalation Exposure- Indoor

o 875.1600 Data Reporting and Calculations

o 875.1700 Product Use Information

• For more information, please refer to Calcium Oxides (Calcium Oxide and Calcium 

Hydroxide): Human Health Assessment Scoping Document in Support of Registration 

Review, located in the docket.

Product Chemistry Data Needs

• The Agency does not anticipate the need to require additional product chemistry data for this

registration review at this time.

• For more information, please refer to Preliminary Plan for Registration Review of: Calcium 

Hydroxide/Calcium Oxide, located in the docket.

Incidents: 

Ecological: 

• No calcium oxide or calcium hydroxide ecological incidents have been reported in the OPP 

incident database.
Docket Number; EPA-HQ-OPP-2010-0693

www.regulations.gov

9

Human Health: 

• The Agency has reviewed the OPP Incident Data Systems (IDS) and one incident associated 

with calcium hydroxide exposure was reported in which dermal and eye irritation were the 

associated symptoms. No incidents associated with calcium oxide exposure have been 

reported. 

Endangered Species

The Agency has not conducted a risk assessment that supports a complete endangered species 

determination for calcium oxide or calcium hydroxide. The ecological risk assessment planned 

during registration review will allow the Agency to determine whether calcium oxide or calcium 

hydroxide’s uses have '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 Wildlife 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. Collectively, 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 endocrine 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 acute tests and 

chronic studies that assess growth, developmental and reproductive effects in different 

taxonomic groups. A human health risk assessment identifying the most sensitive endpoints has 

not been conducted for the Calcium Oxide Case. As required by FFDCA section 408(p), 

calcium oxide and calcium hydroxide are subject to the endocrine screening part of the 

Endocrine Disruptor Screening Program (EDSP). 

EPA has developed the EDSP to determine whether certain substances (including pesticide 

active and other ingredients) may have an effect in humans or wildlife similar to an effect 

produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator 

may designate.” The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine-related effects caused by the substance, and 

establish a dose-response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between 

October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 
Docket Number; EPA-HQ-OPP-2010-0693

www.regulations.gov

10

chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. Calcium oxide 

and calcium hydroxide are 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 calcium 

oxide and calcium hydroxide. For further information 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/.

Timeline

EPA has created the following estimated timeline for the completion of the Calcium Oxide Case 

registration review: 

Anticipated Schedule

Activities Estimated Month/Year

Phase 1: Opening the docket

Open Public Comment Period for Docket Completed

December 2010

Close Public Comment Period for Docket Completed

February 2011

Phase 2: Case Development

Develop Final Work Plan (FWP) Completed

June 2011

Issue DCI June 2012

Data Submission June 2014

Open Public Comment Period for Preliminary Risk Assessments September 2015

Close Public Comment Period for Preliminary Risk Assessments December 2015

Phase 3: Registration Review Decision

Open Public Comment Period for Proposed Reg. Review Decision June 2016

Close Public Comment Period for Proposed Reg. Review Decision September 2016

Final Decision and Begin Post-Decision Follow-up December 2016

Total (years) 6

Next Steps

A DCI will be developed regarding the anticipated data needs listed under the “Risk Assessments 

and Anticipated Data Needs” section of this document. The Agency expects to issue the DCI in 

June 2012. Human health and ecological hazard assessments will be conducted for all registered 

uses of calcium oxide and calcium hydroxide. 
Docket Number; EPA-HQ-OPP-2010-0693

www.regulations.gov

11

V. GLOSSARY of TERMS & ABBREVIATIONS

ai Active Ingredient

AR Anticipated Residue

ASTM American Society for Testing and Materials

AWPA American Wood Preserver’s Association

CBI Confidential Business Information

CFR Code of Federal Regulations

cPAD Chronic Population Adjusted Dose

CSF Confidential Statement of Formula

CSFII USDA Continuing Surveys for Food Intake by Individuals

DCI Data Call-In

DEEM Dietary Exposure Evaluation Model

DFR Dislodgeable Foliar Residue

DNT Developmental Neurotoxicity

DWLOC Drinking Water Level of Comparison

EC Emulsifiable Concentrate Formulation

EDWC Estimated Drinking Water Concentration

EEC Estimated Environmental Concentration

EP End use Product

EPA Environmental Protection Agency

EUP End-Use Product

FDA Food and Drug Administration

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act

FFDCA Federal Food, Drug, and Cosmetic Act

FQPA Food Quality Protection Act

FOB Functional Observation Battery

GENEEC Tier I Surface Water Computer Model

IR Index Reservoir

LC50 Median Lethal Concentration. A statistically derived concentration of a substance that 

can be expected to cause death in 50% of test animals. It is usually expressed as the 

weight of substance per weight or volume of water, air or feed, e.g., mg/l, mg/kg or ppm.

LD50 Median Lethal Dose. A statistically derived single dose that can be expected to cause 

death in 50% of the test animals when administered by the route indicated (oral, dermal, 

inhalation). It is expressed as a weight of substance per unit weight of animal, e.g., 

mg/kg.

LOC Level of Concern

LOAEL Lowest Observed Adverse Effect Level

μg/g Micrograms Per Gram

μg/L Micrograms Per Liter

mg/kg/day Milligram Per Kilogram Per Day

mg/L Milligrams Per Liter

MOE Margin of Exposure 

MRID Master Record Identification (number). EPA's system of recording and tracking 

submitted studies.

MUP Manufacturing-Use Product

NA Not Applicable

NAWQA USGS National Ambient Water Quality Assessment

NPDES National Pollutant Discharge Elimination System

NR Not Required

NOAEL No Observed Adverse Effect Level

OPP EPA Office of Pesticide Programs

OPPTS EPA Office of Prevention, Pesticides and Toxic Substances

PAD Population Adjusted Dose

PAIRA Pure Active Ingredient Radiolabelled
Docket Number; EPA-HQ-OPP-2010-0693

www.regulations.gov

12

PCA Percent Crop Area

PDP USDA Pesticide Data Program

PHED Pesticide Handler's Exposure Data 

PHI Preharvest Interval

phr Pounds Per Hundred

ppb Parts Per Billion

PPE Personal Protective Equipment

ppm Parts Per Million

PRZM/EXAMS Tier II Surface Water Computer Model 

Q1* The Carcinogenic Potential of a Compound, Quantified by the EPA's Cancer Risk Model

RAC Raw Agriculture Commodity

RED Reregistration Eligibility Decision

REI Restricted Entry Interval

RfD Reference Dose

RQ Risk Quotient

RTU Ready to Use

SCI-GROW Tier I Ground Water Computer Model

SAP Science Advisory Panel

SF Safety Factor

SLN Special Local Need (Registrations Under Section 24©) of FIFRA)

TGAI Technical Grade Active Ingredient

TEP Typical End-Use Product

USDA United States Department of Agriculture

UF Uncertainty Factor

WPS Worker Protection Standard