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The EPA/OPPT Work Plan Risk Assessment for 1-Bromopropane (1-BP)

Peer Review Charge Questions

Peer review charge questions are categorized into five main themes:

 General issues on the Risk Assessment

 Occupational Exposure Assessment

 Consumer Exposure Assessment

 Hazard and Dose-Response Assessments

 Risk Characterization

General Issues on the Risk Assessment

EPA/OPPT identified 1-BP as part of the TSCA Work Plan based on high hazard concerns,

industrial use profiles which include scenarios with high exposure for workers, and concernsfor

consumer exposure due to chemical volatility and high content of 1-BP withmost consumer

products contentsranging between 60-100%.

Based on the physical-chemical properties and use scenarios described in this assessment,

EPA/OPPT expects inhalation to be the primary exposure route of concern for 1-BP. Because of

limited toxicological data and the lack of toxicokinetic information needed to develop

physiologically-based pharmacokinetic modelsforroute-to-route extrapolations, EPA/OPPT did

not evaluate dermal exposures.

1-BP exhibits a low ecological hazard profile and low persistence and bioaccumulation potential

if released into aquatic or terrestrial environments. Therefore, a quantitative assessment of

environmental risks was not included in this assessment.

Question 1-1: Please comment on whether the information provided in Section 1 (Background

and Scope) is appropriate and accurately characterizesthe fit for purpose nature of this

assessment for TSCA related uses? Please provide any specific suggestionsfor improving the

clarity and transparency of the background information that describes scope and limits of the

assessment.

Question 1-2: Please comment on the scope of the assessment, in particular the conceptual

model resulting from EPA/OPPT’s problem formulation. Please provide any othersignificant

literature, reports, or data that would be useful to complete this characterization and that may

support expansion or refinement of the scope of this assessment.

Occupational Exposure Assessment

EPA/OPPT evaluated acute and chronic inhalation exposuresto workers using 1-BP in

degreasing (vapor, cold cleaning, and aerosol), spray adhesives and dry cleaning (used in drycleaning machines and spot cleaning). For each of the exposure pathways included in the

assessment, EPA/OPPT quantified occupational exposures based on a combination of
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monitoring data and modeled exposure concentrations. Inhalation exposures were assessed for

both workers and occupational non-users.

EPA/OPPT assessed risksfor workers using 1-BP following acute and chronic exposuresin

degreasing,spray adhesives and dry cleaning. EPA/OPPT assumed that workers would be adults

of both sexes(>16 and older, including pregnant workers) based on occupational work permits,

although exposuresto younger workersin occupational settings cannot be ruled out. Most

monitoring data sources did not indicate whether exposure concentrations were for

occupational users or nonusers. Therefore, EPA/OPPT assumed that occupational exposures

were for a combination of users and nonusers when not specified.

EPA/OPPT assumed that direct contact or close proximity to the use would likely provide the

highest exposuresto 1-BP (i.e., for a commercial application with substantial frequency or

duration of exposure).

Question 2-1: Please comment on the approaches used, and provide any specific suggestions or

recommendationsfor alternative approaches, models, or information (references) that could 

be considered by EPA/OPPT for improving the workplace exposure assessment, including

estimationsfor bystander/non-users(e.g., women of child-bearing age).

Question 2-2: Please comment on whether there are any additional occupational exposure

scenariosthat EPA/OPPT could addressthat have not already been quantified. Please also

provide specific references and/or data to address such additional exposures.

Question 2-3: For the exposure assessments based on monitoring data, are you aware of any

additionalsources of occupational exposure monitoring data that EPA/OPPT could consider in

its assessment? Ifso, please provide specific literature, reports, or data that would help us

refine the exposure assessment.

Question 2-4: For the exposure assessments based on modeling, are you aware of any

additionalsources of data that EPA/OPPT could consider in deriving the parameter values used

in the modeling? Ifso, please provide relevant literature, reports, or data that would help us

refine the parameters used in the modeling

Consumer Exposure Assessment

Because of the relatively short half-life of 1-BP and its expected use pattern in consumer

products, acute exposures to consumers using 1-BP in aerosolspray adhesives, aerosolspot

removers and aerosolspray degreasers and cleaners were evaluated in this assessment.

EPA/OPPT used data from literature sources where available. In the absence of data, EPA/OPPT

relied on use patterns, physical-chemical properties of 1-BP and the Consumer Exposure

Module of the Exposure and Fate Assessment Screening Tool or E-FAST to estimate acute

exposure for consumers.
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EPA/OPPT examined risksfor consumers in residentialsettingsfollowing acute exposures.

EPA/OPPT assumed that consumer users would be adult individuals (>16 and older; including

pregnant women) that intermittently use 1-BP, although exposuresto younger users may be

possible in residential settings. Bystanders would be individuals of any age group (e.g., children,

adults, elderly) who are in a nearby area during product application.

EPA/OPPT assumed that direct contact or close proximity to the use would likely provide the

highest exposuresto 1-BP (i.e., for a consumer with substantial frequency or duration of

exposure).

Question 3-1: Please comment on the approach used and provide any specific suggestions or

recommendationsfor alternative approaches,models, or use information (e.g., information on

duration, number of user events, amount used) that could be considered by EPA/OPPT in

developing and/orrefiningthe exposure assumptions and estimatesforspray adhesives,

aerosol spot removers and aerosolspray cleaners and degreasers.

Question 3-2: Exposure estimates were developed for three consumer uses:spray adhesives,

aerosol spot removers and aerosol spray cleaners and degreasers. All products are aerosol

sprays and appear to be available for sale and use by consumersin the U.S. There were no

current reliable data regarding the consumer exposure scenarios. Please comment on the

consumer uses selected for this assessment and provide any specific suggestions or

recommendationsfor additional uses(including information on duration, number of user

events, amount used) that could be considered for evaluation.

Hazard and Dose-Response Assessments

For hazard identification and dose-response, EPA/OPPT reviewed the evidence for 1-BP toxicity

and selected livertoxicity, kidney toxicity, reproductive/developmental toxicity, neurotoxicity,

and cancer, that taken as a whole, demonstrated the most robust,sensitive and consistent

adverse human health effectsfor risk characterization. EPA/OPPT used benchmark dose (BMD)

modeling where practicable and, when BMD values were adequate, they were used to generate

the POD for characterizing chronic and acute exposure scenarios. EPA/OPPT determined that

using developmental toxicity and neurotoxicity endpointsfor dose-response calculation would

be protective of the most sensitive life stages, including the developing fetusfor non-cancer

points of departure and risk estimates.

For the cancer risk assessment, EPA/OPPT derived the inhalation unit risk (IUR) based on lung

tumorsin female mice. The exact mechanism/mode of action of 1-BP carcinogenesis is not

clearly understood. There are, however, an abundance of data that may provide a basisfor

weight-of-evidence (WOE) considerations; these include in vitro tests,similarity in metabolism

acrossspecies, SAR and other potential mechanisms of action. Other possible mechanisms of

action – oxidative stress, immunosuppression, and cell proliferation—can act synergistically to

complete the multi-stage process of carcinogenesis. Per EPA Guidelinesfor Carcinogen Risk

Assessment, overall, the totality of the available data/information and the WOE analysis for the
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cancer endpoint wassufficient to support a probable mutagenic mode of action for 1-BP

carcinogenesis.

Question 4-1: EPA/OPPT concluded in the risk assessment that 1-BP carcinogenesis occurs

through a probable mutagenic mode of action based on the totality of the available

data/information and the WOE. Please comment whether the cancer hazard assessment has

adequately described the WOE regarding the mutagenic mode of action.

Question 4-2: EPA/OPPT identified livertoxicity, kidney toxicity, reproductive/developmental

toxicity, and neurotoxicity in the risk assessment as adverse human health effectsfor risk

characterization. EPA/OPPT used these endpointsto calculate PODsto assess non-cancer risks

associated with chronic inhalation exposures. As part of the review, please comment on the

choice of these endpoints as PODsfor assessing risks in humans associated with acute and

chronic inhalation exposuresto 1-BP. Are there other data that EPA/OPPT could have

considered for the hazard identification and dose response associated with chronic inhalation

exposures? Ifso, please provide specific data and references.

Question 4-3: Please comment on the WOE analysis for the choices of non-cancer endpointsfor

the acute and chronic risk scenarios. Please provide additional data, data interpretation or

information that would have informed the WOE analysis and selection of critical studies for the

PODs.

Question 4-4: Typically, EPA usesthe benchmark dose modeling software (BMDS) with a

benchmark response(BMR) of 10% and themodels are restricted tomultistagemodels orthe

broadersuite of dichotomous models in BMDS and a single best model is chosen for the POD.

EPA/OPPT used an alternative approach to calculate the cancer POD versusthe standard

approach of choosing best fit model. Briefly, EPA/OPPT used a model averaging approach

considering multiple benchmark dose modelsto calculate the POD at a benchmark response 

(BMR) level of 0.1%. Please comment on the assumptions, strengths and weaknesses of the

model averaging approach for determining the POD in the cancer assessment.

Risk Characterization

EPA/OPPT quantified non-cancer risks based on the Margin of Exposure (MOE), which isthe

product of dividing the scenario specific exposure into the hazard point of departure which is

the no adverse effect level, based on animal and/or human studies. EPA/OPPT calculated MOEs

for acute or chronic exposuresseparately based on the appropriate non-cancer POD and

estimated exposure concentrations adjusted for durations. To determine if unacceptable risks

were present for relevant exposure scenarios, the endpoint-specific MOEs were compared to

the endpoint-specific benchmark MOEs. The benchmark MOEs were the product of all of the

relevant UFsidentified for each non-cancer POD. If the MOE estimate was lessthan the

benchmark MOE, the exposure scenario for non-cancer endpoints wasinterpreted as a human

health risk.

Cancer risk estimation consisted of multiplying the occupationalscenario-specific exposure

estimates by the cancer IUR to estimate the added cancer risk. Added lifetime cancer risk
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estimates from 1-BP exposure were compared to benchmark cancer risk levels of 10-4, 10-5and 10-6

(i.e., 1 in10,000,1in100,000 and1in1,000,000).

Question 5-1: EPA/OPPT interpreted the endpoint of decreases in live littersize following

exposure to 1-BP before and during gestation, as a surrogate for frank developmental effects

relevant to humans per EPA’s Guidelinesfor Developmental Toxicity Risk Assessment.

EPA/OPPT used this endpoint to calculate a point of departure (POD) to assess non-cancer risks

associated with acute inhalation exposuresto 1-BP. Please comment on the assumptions,

strengths and weaknesses of the MOE approaches used to estimate the non-cancer risksto

workers and occupational non-usersfollowing acute inhalation exposuresto 1-BP, including the

MOEs presented in the document. Please comment on the assumptions,strengths and

weaknesses of the MOE approaches used to estimate risks to consumersfollowing acute

inhalation exposures; including non-users (e.g., bystanders who may be children, or women of

childbearing age). Specifically, please comment on the decision to limit the analysis to acute

exposures without residual concerns between events and what data could critically inform

modifying this approach for consumers. Please comment on the selection of uncertainty factor

values in deriving the benchmark MOE for acute inhalation exposures.

Question 5-2: Please comment on the assumptions, strengths and weaknesses of the MOE

approaches used to estimate the non-cancer risksto workers and occupational non-users

following chronic inhalation exposuresto 1-BP, including the MOEs presented in the document.

Please comment on the selection of uncertainty factor values in deriving the benchmark MOE

for chronic inhalation exposures.

Question 5-3: Please comment on the assumptions, strengths and weaknesses of the approach

used to estimate added lifetime cancer risks to workers which EPA/OPPT-derived from an

inhalation unit risk based on lung tumors in female mice for estimating incremental or added

individual lifetime cancer risk.

Question 5-4: Please comment on whether the risk characterization has adequately described

the assumptions, uncertainties and data limitations in the methodology used to assessrisks

from 1-BP. Please comment on whether this information and risk conclusions are presented in a

logical, transparent manner and provide suggestions that could increase clarity in the risk

characterization.