February 29, 2016

1



### The EPA/OPPT Work Plan Risk Assessment for 1-Bromop ropane (1-BP)

Draft Peer Review Charge Questions

Peer review charge questions are categorized into f ive 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 P lan based on high hazard concerns, industrial use profiles which include scenarios wit h high exposure for workers, and concerns for consumer exposure due to chemical volatility and hi gh content of 1-BP most consumer products contents ranging between 60-100%.

Based on the physical-chemical properties and use s cenarios described in this assessment, EPA/OPPT expects inhalation to be the primary expos ure route of concern for 1-BP. Because of limited toxicological data and the lack of toxicoki netic information needed to develop physiologically-based pharmacokinetic models for ro ute-to-route extrapolations, EPA/OPPT did not evaluate dermal exposures.

1-BP exhibits a low ecological hazard profile and l ow persistence and bioaccumulation potential if released into aquatic or terrestrial environment s. Therefore, a quantitative assessment of
environmental risks was not included in this assess ment.

Question 1-1: Please comment on whether the informa tion provided in Section 1 (Background and Scope) is appropriate and accurately characteri zes the fit for purpose nature of this assessment for TSCA related uses? Please provide an y specific suggestions for improving the clarity and transparency of the background informat ion that describes scope and limits of the

assessment.

Question 1-2: Please comment on the scope of the as sessment, in particular the conceptual model resulting from EPA/OPPT’s problem formulation . Please provide any other significant literature, reports, or data that would be useful t o complete this characterization and that may support expansion or refinement of the scope of thi s assessment.

Occupational Exposure Assessment EPA/OPPT evaluated acute and chronic inhalation exp osures to workers using 1-BP in degreasing (vapor, cold cleaning, and aerosol), spr ay adhesives and dry cleaning (used in drycleaning machines and spot cleaning). For each of t he exposure pathways included in the assessment, EPA/OPPT quantified occupational exposu res based on a combination ofFebruary 29, 2016

2

monitoring data and modeled exposure concentrations . Inhalation exposures were assessed for both workers and occupational non-users.

EPA/OPPT assessed risks for workers using 1-BP foll owing acute and chronic exposures in degreasing, spray adhesives and dry cleaning. EPA/O PPT assumed that workers would be adults of both sexes (>16 and older, including pregnant wo rkers) based on occupational work permits, although exposures to younger workers in occupation al settings cannot be ruled out. Most monitoring data sources did not indicate whether ex posure concentrations were for occupational users or nonusers. Therefore, EPA/OPPT assumed that occupational exposures
were for a combination of users and nonusers when n ot specified.

EPA/OPPT assumed that direct contact or close proxi mity to the use would likely provide the highest exposures to 1-BP (i.e., for a commercial application with substantial frequ ency or duration of exposure).

Question 2-1: Please comment on the approaches used , and provide any specific suggestions or recommendations for alternative approaches, models, or information (references) that could be considered by EPA/OPPT for improving the workpla ce exposure assessment, including estimations for bystander/non-users (e.g., women of child-bearing age).

Question 2-2: Please comment on whether there are a ny additional occupational exposure scenarios that EPA/OPPT could address that 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 additional sources of occupational exposure monitor ing data that EPA/OPPT could consider in its assessment? If so, please provide specific lite rature, 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 additional sources of data that EPA/OPPT could cons ider in deriving the parameter values used in the modeling? If so, please provide relevant lit erature, 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 a nd its expected use pattern in consumer products, acute exposures to consumers using 1-BP i n aerosol spray adhesives, aerosol spot removers and aerosol spray degreasers and cleaners were evaluated in this assessment. EPA/OPPT used data from literature sources where av ailable. In the absence of data, EPA/OPPT relied on use patterns, physical-chemical propertie s of 1-BP and the Consumer Exposure Module of the Exposure and Fate Assessment Screenin g Tool or E-FAST to estimate acute exposure for consumers.February 29, 2016

3

EPA/OPPT examined risks for consumers in residentia l settings following acute exposures. EPA/OPPT assumed that consumer users would be adult individuals (>16 and older; including pregnant women) that intermittently use 1-BP, altho ugh exposures to 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 pr oduct application.

EPA/OPPT assumed that direct contact or close proxi mity to the use would likely provide the highest exposures to 1-BP (i.e., for a consumer with substantial frequency or durati on of exposure).

Question 3-1: Please comment on the approach used a nd provide any specific suggestions or recommendations for 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 /or refining the exposure assumption s and estimates for spray adhesives, aerosol spot removers and aerosol spray cleaners an d degreasers.

Question 3-2: Exposure estimates were developed for three consumer uses: spray adhesives, aerosol spot removers and aerosol spray cleaners an d degreasers. All products are aerosol sprays and appear to be available for sale and use by consumers in the U.S. There were no current reliable data regarding the consumer exposu re scenarios. Please comment on the consumer uses selected for this assessment and prov ide any specific suggestions or recommendations for additional uses (including info rmation on duration, number of user events, amount used) that could be considered for e valuation.

Hazard and Dose-Response Assessments For hazard identification and dose-response, EPA/OP PT reviewed the evidence for 1-BP toxicity and selected liver toxicity, kidney toxicity, repro ductive/developmental toxicity, neurotoxicity, and cancer, that taken as a whole, demonstrated the most robust, sensitive and consistent
adverse human health effects for risk characterizat ion. EPA/OPPT used benchmark dose (BMD) modeling where practicable and, when BMD values wer e adequate, they were used to generate the POD for characterizing chronic and acute exposu re scenarios. EPA/OPPT determined that using developmental toxicity and neurotoxicity endp oints for dose-response calculation would be protective of the most sensitive life stages, in cluding the developing fetus for non-cancer points of departure and risk estimates.

For the cancer risk assessment, EPA/OPPT derived th e inhalation unit risk (IUR) based on lung tumors in female mice. The exact mechanism/mode of action of 1-BP carcinogenesis is not clearly understood. There are, however, an abundanc e of data that may provide a basis for weight-of-evidence (WOE) considerations; these incl ude in vitro tests, similarity in metabolism across species, SAR and other potential mechanisms of action. Other possible mechanisms of action – oxidative stress, immunosuppression, and c ell proliferation—can act synergistically to complete the multi-stage process of carcinogenesis. Per EPA Guidelines for Carcinogen Risk

Assessment , overall, the totality of the available data/infor mation and the WOE analysis for theFebruary 29, 2016

4

cancer endpoint was sufficient to support a probabl e mutagenic mode of action for 1-BP carcinogenesis.

Question 4-1: EPA/OPPT concluded in the risk assess ment that 1-BP carcinogenesis occurs through a probable mutagenic mode of action based o n the totality of the available data/information and the WOE. Please comment whethe r the cancer hazard assessment has adequately described the WOE regarding the mutageni c mode of action.

Question 4-2: EPA/OPPT identified liver toxicity, k idney toxicity, reproductive/developmental toxicity, and neurotoxicity in the risk assessment as adverse human health effects for risk characterization. EPA/OPPT used these endpoints to calculate PODs to assess non-cancer risks associated with chronic inhalation exposures. As pa rt of the review, please comment on the choice of these endpoints as PODs for assessing ris ks in humans associated with acute and chronic inhalation exposures to 1-BP. Are there oth er data that EPA/OPPT could have
considered for the hazard identification and dose r esponse associated with chronic inhalation exposures? If so, please provide specific data and references.

Question 4-3: Please comment on the WOE analysis fo r the choices of non-cancer endpoints for the acute and chronic risk scenarios. Please provid e additional data, data interpretation or information that would have informed the WOE analys is and selection of critical studies for the

PODs.

Question 4-4: Typically, EPA uses the benchmark dos e modeling software (BMDS) with a BMR of 10% and the models are restricted to multistage models or the broader suite of dichotomous models in BMDS and a single best model is chosen fo r the POD. EPA/OPPT used an alternative approach to calculate the cancer POD versus the sta ndard approach of choosing best fit model. Briefly, EPA/OPPT used a model averaging approach c onsidering multiple benchmark dose models to calculate the POD at a benchmark response (BMR) level of 0.1%. Please comment on the assumptions, strengths and weaknesses of the mo del averaging approach for determining
the POD in the cancer assessment.

Risk Characterization EPA/OPPT quantified non-cancer risks based on the M argin of Exposure (MOE), which is the product of dividing the scenario specific exposure into the hazard point of departure which is no adverse effect level, based o n animal and/or human studies. EPA/OPPT calculated MOEs for acute or chronic exposures sepa rately based on the appropriate noncancer POD and estimated exposure concentrations ad justed for durations. To determine if unacceptable risks were present for relevant exposu re scenarios, the endpoint-specific MOEs were compared to the endpoint-specific benchmark MO Es. The benchmark MOEs were the product of all of the relevant UFs identified for e ach non-cancer POD. If the MOE estimate was less than the benchmark MOE, the exposure scenario for non-cancer endpoints was interpreted
as a human health risk.

Cancer risk estimation consisted of multiplying the occupational scenario-specific exposure estimates by the cancer IUR to estimate the added c ancer risk. Added lifetime cancer riskFebruary 29, 2016

5

estimates from 1-BP exposure were compared to benchmark cancer risk levels of 10 -6 , 10 -5 and 10 -4
(i.e., 1 in 10,000, 1 in 100,000 and 1 in 1,000,000 ).

Question 5-1: EPA/OPPT interpreted the endpoint of decreases in live litter size following exposure to 1-BP before and during gestation, as a surrogate for frank developmental effects in relevant to humans per EPA’s Guidelines for Developmental Toxicity Risk Assessme nt

. EPA/OPPT used this endpoint to calculate a point of departure (POD) to assess non-cancer risks associated with acute inhalation exposures to 1-BP. Please comment on the assumptions, strengths and weaknesses of the MOE approaches used to estimate the non-cancer risks to workers and occupational non-users following acute inhalation exposures to 1-BP, including the MOEs presented in the document. Please comment on t he assumptions, strengths and weaknesses of the MOE approaches used to estimate r isks to consumers following acute inhalation exposures; including non-users (e.g., by standers 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 comme nt on the selection of uncertainty factor values in deriving the benchmark MOE for acute inha lation exposures.

Question 5-2: Please comment on the assumptions, st rengths and weaknesses of the MOE approaches used to estimate the non-cancer risks to workers and occupational non-users following chronic inhalation exposures to 1-BP, inc luding the MOEs presented in the document. Please comment on the selection of uncertainty fact or values in deriving the benchmark MOE for chronic inhalation exposures.

Question 5-3: Please comment on the assumptions, st rengths and weaknesses of the approach
used to estimate added lifetime cancer risks to wor kers 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 ch aracterization has adequately described the assumptions, uncertainties and data limitations in the methodology used to assess risks
from 1-BP. Please comment on whether this informati on and risk conclusions are presented in a logical, transparent manner and provide suggestions that could increase clarity in the risk
characterization.