1



## Response to Comments Received on the April 15, 2015

Proposed Rule (80 FR 20189):

Addition of 1

- Bromopropane; Community Right

- to

- Know Toxic

Chemical Release Reporting

August 20 , 2015

U.S. Environmental Protection Agency

Office of Information Analysis and Access

William Jefferson Clinton Federal Building

1200 Pennsylvania Ave., NW

Washington, DC 204602

Note that in some of the comments 1

- bromopropane is referred to as nPB

, which is the acronym for the alternative chemical name n

- propyl bromide.

Comment er: Albemarle Corporation

The majority of comments provided by Albemarle are the same comments they submit ted in response to the “R eceipt of a complete petition ” to add 1

- bromopropane to the Hazardous Air Pollutant (HAP) List (80 FR 6676, February 6, 2015)

. The Docket Number for the petition to

add 1

- bromopropane to the HAP list is EPA

- HQ

- OAR

- 2014

- 0471

- 0001

. The only comments specific to EPA’s proposed rule to add 1

- bromopropane to the EPCRA section 313 chemical list

were pr ovided in a letter from Charles R. Nestrud of the law firm Chisenhall, Nestrud & Julian,

P.A. dated June 10, 2015 (Nest r ud letter). EPA is providing responses to all of the comments in

the Nestrud letter.

The vast majority of the comments submitted by Albemarle on the HAP listing petition

dealt with issue s of emissions, exposure
, risk values, and risk assessment , which are not relevant to the proposed listing of 1

- bromopropane to the EPCRA section 313 chemical list since the listing is based on hazard and not risk. The addition of 1

- bromopropane to the EPCRA section 313 chemical list is based on the cancer hazard evaluation carried out by the National Toxicology Program (NTP) and reviewed by EPA to ensure its consi stency with the EPA Guidelines for Carcinogen Risk Assessment (U.S. EPA 20 05a). Consistent with the EPA

g uidelines (U.S. EPA 2005a), the NTP 13 th Report on Carcinogens (RoC) (NTP 2014) evaluates the scientific literature and publicly available, peer

- revie wed technical reports of human and laboratory studies to evaluate whether substances are possible human carcinogens. The NTP RoC does not present a quantitative assessment of the risks of cancer associated with a given chemical. Rather, it indicates the p otential hazard associated with chemicals but does not establish the exposure conditions that would pose cancer risks to individuals. In the 13 th RoC,

the NTP classified 1

- bromopropane as “reasonably anticipated to be a human carcinogen.” The

conclusions of the NTP 13 th RoC for 1

- bromopropane were consistent with how EPA would consider the carcinogenicity data available for 1

- bromopropane. Therefore, for the purposes of listing 1

- bromopropane on the EPCRA section 313 chemical list, EPA concluded that 1

- b romopropane can reasonably be anticipated to cause cancer in humans. Since the listing of 1

- bromopropane under EPCRA section 313 is based on the available cancer data alone , EPA is not responding to the comments from Albemarle Corporation on the HAP listing petition that dealt with issues of emissions, exposure, risk values, and risk assessment.

While not specific to the materials EPA cited to support the addition of 1

- bromopropane

to the EPCR A section 313 chemical list, there were some comments on the cancer data for 1

- bromopropane in the materials that Albemarle submitted in response to the HAP listing petition. Specifically, these comments are contained in sections 2.2 and 2.3 of the document “ Comments

on the P etition to Add n

- Propyl Bromide to the List of Haz ardous Air Pollutants Regulated under § 112 of the Clean Air Act ” prepared by the Gradient Corporation (Gradient Corp.). Since these comments dealt with the toxic endpoint (cancer) that is the basis for the addition of 1

- bromopropane to the EPCRA section 313 chemi cals list, EPA has addressed the se comments as
well.3

Comment: Nest r ud letter

“ The comments prepared by Albemarle and its consultants demonstrate that the technical information submitted to support the Proposed Rule is out of date, incorrect, and

insufficient to support the Proposed Rule. Furthermore, when all toxicological data is considered, and current emission data is considered, the weight of the evidence does not support adding 1

- bromopropane to the list of toxic chemicals. ”

Response: EPA disagrees that the information submitted to support the propose d rule to add 1

- bromopropane to the EPCRA section 313 chemical list is “out of date, incorrect, and insufficient to support the Proposed Rule.” EPA provided information from the NTP 13 th RoC which was released on October 2, 2014. EPA’s evaluation of the d ata used to support the findings for 1

- bromopropane was conducted shortly after the release of the 13 th RoC and completed on November 3, 2014 . EPA’s economic analysis of the potential costs of the proposed rule including the estimate of the number of faci lities expected to file reports was completed on February 17, 2015. EPA notes that the commenter did not provide any comments specific to

EPA’s evaluation of the NTP 13 th RoC data and findings for 1

- bromopropane (reference 6 in the propose rule) , or specific to the NTP 13 th RoC materials prepared for 1

- bromopropane (references 5 and 7 in the propose rule) , or on EPA ’s economic analysis for the addition of 1

- bromopropane (reference 8 in the proposed rule)

. It is

, therefore

, unclear which technical

inf ormation that EPA submitted to support the proposed rule that the commenter believes is out of date, incorrect, or insufficient to support the propose d rule. Comments regarding the available

cancer data and relevance of emissions data are discussed in other responses below.

Comment: Nest r ud letter

“In its 1994 rulemaking EPA identified certain criter ia it had developed to evaluate

chemicals for additions to the list of toxic chemicals. This inc luded a toxicity and production volume screen, and a hazard evaluation based on the init ial screen. Addition

of Certain Chemicals; Toxic Chemical Release Reporting; Community Rig ht

- to

- Know; Final Rule (59 Fed. Reg. No. 229; Doc. No. 94

- 29376, November 30, 1994; OPPTS

400082 B

.

Toxicity Screen. Through t he toxicity screen a chemical is assigned a "high priority," "medium priority," or "low priority." The attached comments submitted to EPA as part of the nPB Petition demonstrate that there is insufficient toxicity inf ormation to support assigning a "hi gh priority," or "medium priority" to nPB.”

EPA Response: The information that the commenter has cited regarding the criteria EPA identified for evaluating chemicals for addition to the EPCRA section 313 chemical list are the criteria EPA

used for its 19 94 chemical expansion rulemaking to evaluate large numbers of chemicals for potential addition . These screening criteria are not the criteria used to determine whether or not4

a chemical can be added to the EPCRA section 313 chemical list , that criteria is established under EPCRA section 313(d)(2). As EPA noted in the 1994 chemical expansion rule:

“A toxicity screen is a limited review of readily available toxicity data that is used for a preliminary categorization of a chemical during the process of selecting candidates for possible listing under EPCRA section 313. The toxicity screen is used to identify chemicals for further consideration and does not reflect a final determination for listing a

chemical under EPCRA section 313. S uch a determination can only be made after a hazard assessment is conducted (See Unit 11.3. of this preamble).” ( 59 FR 61433, November 30, 1994)

EPA did not screen 1

- bromopropane for addition, but rather conducted a hazard

evaluation of the a vailable cancer data and based on the classifi cation by the NTP in their 13 th RoC as “reasonably anticipated to be a human carcinogen” and our review of that data,

concluded 1

- bromopropane should be added to the EPCRA section 313 chemical list

. As noted in the pro posed rule, EPA reviewed the data used by the NTP to make this determination and agreed with the NTP’s classification (reference 6 in the proposed rule ) . As EPA noted in the 1994 chemical expansion rule, cancer is an extreme toxic effect:

“In some cases the effects are extreme, such as cancer or death.” (59 FR 61433, November 30, 1994)

If EPA had conducted a toxicity screen like that used in the 1994 chemical expansion rule, the

available cancer data would have been sufficient to classi fy 1

- bromopropane as a high priority for listing. In fact, the NTP’s 6 th RoC was a primary source reviewed for chemicals fo r potential addition (59 FR 1789, January 12, 1994)

. As previously noted, the commenter did not provide any comments specifically o n the NTP’s classification of 1

- bromopropane as “reasonably anticipated to be a human carcinogen” in the 13 th RoC nor did they provide any comments on

EPA ’s evaluation of the NTP cancer data and classification as provide d in r eference 6 of the proposed rule (80 FR 20189, April 15, 2015).

Comment: Nest r ud letter

“ Production Volume Screen. When use of the chemical is less than the reporting thresholds, the chemical is "not considered further." The attached comments submitted to EPA as part of the nPB Petition demonstrate that there are no facilities in the dry cleaning or spray adhesives industries that use more 1

- bromopropane than the reporting threshold of 10,000 pounds (5 tons). Although the nPB Petition identified one facility in the metal cleaning industry that used more 1

- bromopropane than the reporting threshold of 10,000 pounds (5 tons), that facility reported its use of nPB pursuant to its Title V Air

Permit.”

EPA Response:

Reference 8 in the proposed rule was the economic analysis for the addition of 1

- bromopropane to the EPCRA section 313 chemical list. As indicated in the economic analysis,

EPA estimates that 140 reports (126 F orm Rs and 14 Form As) from 23 different indu stry sectors5

will be filed for 1

- bromopropane . Therefore

, EPA has determined that there is sufficient production and use of 1

- bromopropane such that re ports will be filed. As previously noted, the commenter provided no specific comments on EPA ’s economic analysis. C ertain spray adhesives industries may be required to report under EPCRA section 313

, but dry cleaning facilities are not a covered industry sector and thus are not required to file reports under EPCRA

section 313. While it has been E PA’s policy to focus on the addition of chemicals for which reports are expected to be filed, it is not a statutory requirement. As EPA noted in the 2010 proposed rule for the addition of 16 NTP carci nogens to the EPCRA section 313 chemical list :

“ Secti on 313(d)(2) of EPCRA provides EPA the discretion to add chemicals to the TRI list when there is sufficient evidence to establish any of the listing criteria. EPA can add a chemical that meets one criterion regardless of its production volume. ” (75 FR 17336, April 6, 2010)

Comment: Nest r ud letter

“ Hazard Evaluation. Based on the results of the screen, EPA should conduct a Hazard

Evaluation for 1

- bromopropane. The attached comments submitted to EPA as part of the

nPB Petition demonstrate that the weight of the evidence is not sufficient to add 1

- bromopropane to the list of toxic chemicals. In particular, the individual lifetime cancer risk at maximally impacted census receptors near the facilities that use 1

- bromopropane

is less than 1 in 1 million for all the facilities identified by EPA in the nPB Petition, with the exception of a narrow tube manufacturing facility, for which the maximum individual

lifetime cancer risk is less than 1 in 100,000. Other than STC, there are no identif ied populations that would have a lifetime cancer risks from exposure to nPB in excess of 1

in 1 million.

Accordingly, there is no information that would support adding 1

- bromopropane

to the list of toxic chemicals.”

EPA Response:

The commenter states that EPA should conduct a “Hazard Evaluation” for 1

- bromopropane, but t hat is exactly what EPA did . EPA’s hazard evaluation included the NTP’s

classification of 1

- bromopropane as “reasonably anticipated to be a human carcinogen” and

EPA’s review of the data used by the NTP to support th at classification. As noted in the proposed rule, the NTP conducted an extensive review (including public comment and peer review) of the cancer data for 1

- bromopropane in making the classification for the NTP 13 th

R oC. EPA’s review of that information, as discussed in reference 6 of the proposed rule,

concluded that:

“The conclusions of the NTP RoC for 1

- bromopropane were consistent with how the Agency would consider the carcinogenicity data available for 1

- bromo propane. Therefore, it would be appropriate for the Agency, for the purposes of listing 1

- bromopropane on the Toxics Release Inventory, to conclude that 1

- bromopropane can reasonably be anticipated to cause cancer in humans. ”6

EPA believes the cancer data for 1

- bromopropane sufficient ly support listing under EPCRA section 313(d)(2) (B) . None of the information concerning the cancer data that the commenter submitted in their response to the petition to add 1

- bromopropane to the hazardous air pol lutant (HAP) list changes EPA’s conclusion with regard to the potential for 1

- bromopropane to cause cancer in humans. Responses to the specific comments on certain portions of the hazard

evaluation are address ed elsewhere in this document.

With regard s t o the commenter ’ s conclusions concerning the cancer risks from facilities identified in the HAP petition, this information is not relevant to the addition of 1

- bromopropane

to the EPCRA section 313 chem ical list. EPA did not base the propose d addition of 1

- bromopropane to the EPCRA section 313 chemical list on any exposure or risk evaluation. 1

- Bromopropane meets the EPCRA section 313 (d)(2)(B) listing criteria based on the cancer data alone and there are no statutory requirements to consider exposure o r risk under EPCRA section 313(d)(2)(B). While the statutory criteria of EPCRA section 313(d)(2)(B) do not require consideration of exposure or risk, EPA has a policy concerning when it may be appropriate to consider potential exposures when adding chemic als under EPCRA section 313(d)(2)( B). As

EPA stated in the proposed rule:

“ EPA considers ch emicals that can reasonably be anticipated to cause cancer to have moderately high to high chronic toxicity. EPA does not believe that it is appropriate to

con sider exposure for chemicals that are moderately high to highly toxic based on a

hazard assessment when determining if a chemical can be added for chronic effects pursuant to EPCRA section 313(d)(2)(B) (see 59 FR 61440

- 61442). Therefore, in

accordance with EPA’s standard policy on the use of exposure assessments (59 FR 61432), EPA doe s not believe that an exposure assessment is necessary or appropriate for determining whe ther 1

- bromopropane meets the criteria of EPCRA section 313(d)(2)(B).”

EPA di sagrees with the conclusion of the commenter that there is no information that would support adding 1

- bromopropane to the EPCRA section 313 chemical list. In fact, it is EPA’s position that there are ext ensive cancer data that support this addition as dis cussed and referenced in the proposed rule

.

With regards to the listing of 1

- bromopropane as a HAP, the 1 in 1 million risk level does not apply. Under the Clean Air Act, 1 in 1 million risk applies specifically under section 112 (d) to source categories for residual risk and to section 129 rules.

Comment: Gradient Corp. Comments on HAP Petition

“ 2.2 Human Relevance of Petitioner's Inhalation Unit Risk Factor

The petitioners' risk assessment is based on alveolar/bronchiolar adenomas and

carcinomas in B6C3F1 mice, reported by NTP (2011). The petitioners suggest, "there are no reasons to assume that the mode, or modes, of action by which tumors are induced by nPB are not relevant to man" (Patton Boggs, 2010). However, the sup porting7

information that the petitioners include for this statement lacks an analysis of the human relevance of the mouse lung tumors or any other cancer endpoint. US EPA (2005a)

recommends collecting relevant information on the mode of action ( i.e. , the key biological events leading to the adverse health effect) when evaluating chemical hazards.

US EPA's Guidelines for Carcinogen Risk Assessment recommends evaluating whether:

1. The hypothesized mode of action is sufficiently supported in test

animals ; 2. The hypothesized mode of action is relevant to humans; and 3. Sensitive populations or lifestages are susceptible to the hypothesized mode of action (US EPA, 2005a).

These considerations are necessary to characterize the overall weight of evidence to support the hypothesis for causation of a health effect from exposure to a chemical. Further, the process for evaluating these questions during cancer risk assessment and the development of toxicological criteria ( e.g. , reference concentration s, reference doses, and IUR estimates) under the Integrated Risk Information System (IRIS) is required by US EPA (2005a, 2013).

This particular mouse tumor type (alveolar/bronchiolar adenomas and carcinomas) has

been reviewed and debated for a number of chemical compounds and was the subject of a 2014 technical workshop sponsored by US EPA (see reviews by US EPA, 2014; Cruzan

et al. , 2009; Edler et al. , 2014; Moore et al. , 2013). For example, relevant information is available for nPB to explore the afore mentioned mode

- of

- action questions:

 The results of the NTP (2011; Morgan et al. , 2011) study for nPB yielded

inconsistent results across test species (mice and rats). NTP reported a significant

increase in alveolar/bronchial adenomas or carcinomas in fe male mice, but no significant changes in male mice or male and female rats. NTP (Moore et al.

, 2013) performed a review of this tumor type for all NTP studies conducted over 30 years and found that the incidence of these lesions (relative to background) is greater in female mice than in male mice. Further, NTP (Moore et al. , 2013) suggested that female mice may have a limited capacity for tumor defense or repair and a greater susceptibility to environmental stressors, and that their tumor response may be age

- dependent. Thus, due to the sensitivity of female mice, there is a potential for this endpoint to over

- predict a carcinogenic response in

humans.

 Similarly inconsistent results between rodent species have been noted for other volatile organic chemi cals ( e.g. , naphthalene, styrene, ethylbenzene, cumene), which has led to investigations on the human relevance of mouse lung tumors (US EPA, 2014; Cruzan et al. , 2009). During the US EPA workshop deliberations, key differences were noted between mice, ra ts, and humans with respect to lung physiology, metabolism (pharmacokinetics and pharmacodynamics), and genotoxicity (US EPA, 2014).8  During this US EPA workshop and in a prior publication, Cruzan et al. (2009) proposed that mouse lung tumors are mediated through a mouse

- specific metabolic pathway that induces a nongenotoxic and cytotoxic mode of action that is irrelevant to human lung toxicity and cancer. The activity of cytochromes P450 (specifically CYP2F) is greater in the mouse lung than in the rat o r human lung (Cruzan et al. , 2009; US EPA, 2014). Thus, Cruzan et al. (2009) hypothesized that, in the mouse lung, chemical

- induced cytotoxicity from chronic inflammation and subsequent regenerative hyperplasia leads to an increase in mostly benign lung tumors. NTP (2011) reported a dose

- related presence of lung bronchiole regeneration in mice, which is consistent with chronic inflammation, cytotoxicity, and cellular repair. If indeed the mode of action is non

- genotoxic, then the default linear threshold model used by the petitioners to estimate the IUR may not be appropri ate, and a non

- linear (threshold) approach may provide a more accurate representation of the dose

- response relationship between nPB exposure and cancer endpoints (US EPA, 2005a 2014).

 Finally, the workshop documented a number of uncertainties regarding t he relevance of mouse lung tumors for human health and identified several areas for future research (US EPA, 2014).

Therefore, counter to the petitioners' assumptions, there is evidence that the mode of

action for the endpoint selected to predict risks for nPB may not be relevant for humans. Considering the state of the science surrounding this health endpoint, US EPA should not rely on the data for alveolar/bronchiolar adenomas and carcinomas in B6C3F1 mice for

charac terizing cancer risks in humans from exposure to nPB. Further, the use of the linear multistage dose

- response model assumes a mutagenic mode of action, which has not been demonstrated for nPB; instead, a threshold, non

- linear model may be more appropriate for conducting nPB cancer risk assessment. ”

EPA Response: As EPA previously noted, the proposed addition of 1

- bromopropane to the EPCRA

section 313 chemical list is based on hazard alone and not on any consideration of exposures or potential risks. For the purposes of listing under EPCRA section 313(d)(2)(B) , EPA is not relying on the data for alveolar/bronchiolar adenomas and carcinomas in B6C3F1 mice for characterizing cancer risks in humans from exposure to 1

- bromopropane. While EPA convened

a te chnical workshop on the stat e

- of

- the

- science for chemically

- induced mouse lung tumors, there was no consensus on the relevance of this tumor to humans (U.S. EPA 2014). Rather, one of the workshop outcomes included the future application of the information discussed during the workshop to develop a mode of action framework on a chemical by chemical basis. As stated in the EPA Guidelines for Carcinogen Ri sk Assessment (U.S. EPA 2005a):

“The default option is that positive effects in animal cancer studies indicate that the agent under study can have carcinogenic potential in humans. Thus, if no adequate human or mode of action data are present, positive effects in animal cancer studies are a basis for assessing the carcinogenic hazard to humans.”9

The N TP monograph for 1

- bromopropane ( NTP 2013 ) discussed the issue of mode of action in

the section on mechanistic considerations :

“5.3 Mechanistic considerations

The biological events associated with chemically induced cancer are not completely

understoo d even for chemicals that have been extensively studied and are known to cause cancer in humans (e.g., benzene and arsenic) (Guyton et al. 2009). It is important to recognize that chemicals can act through multiple toxicity pathways and mechanisms to

i nduce cancer or other health effects, and the relative importance of the various pathways may vary with life stage, genetic background, and dose. Thus, it is unlikely that for any chemical a single mechanism or mode of action will fully explain the mult iple biological alterations and toxicity pathways that can cause normal cells to transform and ultimately

form a tumor.

Although no studies were identified that were specifically designed to investigate possible mod es of action for 1

- bromopropane

- indu ced carcinogenesis, the available data indicate that metabolic activation, genetic damage, and oxidative stress from glutathione depletion are important factors. As discussed in the previous section, these factors were linked to several of the primary non

- neoplastic toxic effects of 1

- bromopropane, including immunosuppression, neurotoxicity, reproductive toxicity, and hepatotoxicity. Other factors that have been associated with carcinogenesis and may be relevant for 1

- bromopropane are discussed and include immune

- response modulation, altered cell signaling and gene expression, inflammation, and cytotoxicity and compensatory cell proliferation. ” (page 40)

After considering the mode of action issues, the NTP classifi ed 1

- bromopropane as “reasonably anticipated to be a human carcinogen.” EPA believes that this classification is consistent with

how the data would be evaluated under EPA’s Guidelines for Carcinogen Risk Assessment (U.S.
EPA 2005a)

.

Comment: Gradient Co rp. Comments on HAP Petition

“ 2.3 Human Relevance of NTP Results

The petitioners cited NTP results for the mouse and rat bioassays as evidence of the potential carcinogenic activity of nPB. However, they did not consider potential

uncertainties found in the underlying mutagenicity, genotoxicity, and carcinogenicity

information for nPB. This is not consistent with US EPA's cancer guidelines, which recommend evaluating the weight of evidence prior to determining the carcinogenic potential of a chemical substance (US EPA, 2005a). Several potential uncertainties are apparent in the underlying toxicological information:10  No epidemiology data are available to support the results from in vitro or in vivo toxicity tests for nPB (NTP, 2011). Therefore, the results from these experimental studies are not verifiable in humans.

 Only one long

- term bioassay that evaluated carcinogenic activity is available; its

results are inconsistent between species and sex, and the dose

- response relationships it reports are not strong in all cases (NTP, 2011). Further, as discussed above, in Section 2.2, the lung tumor results from this bioassay may not be relevant for predicting carcinogenicity in humans.

 NTP (2011) focused on the results of one positive in vitro mutageni city assay (Ames test) as support for the potential of nPB to be a human carcinogen. However, when considering all the available results of in vitro and in vivo tests of nPB's genotoxicity (see Tables 2.4 and 2.5), the majority of those results are negati ve. For example, seven in vitro bacterial mutagenicity (Ames) tests have been performed using nPB (Table 2.4). These include recent tests conducted by

NTP (2011) and BioReliance (2014; see Attachment B). These tests include multiple strains, using currently accepted test methods, and both open and closed test systems (due to the volatility of nPB). Only one test (Barber et al. , 1981) yielded a positive result in the Ames test. In addition, Barber et al. noted that the

limit of detection in the ass ay using nPB was 31.2 ppm (for strain TA1535) and 106.5 ppm (for strain TA100). Thus, the results from Barber et al. (1981) are only reliable at vapor concentrations above ~30 ppm, which is several orders of magnitude greater than concentrations found in ambient air (see Section 3).

 Additional mammalian in vitro and in vivo tests are available (summarized in Tables 2.4 and 2.5):

• An in vitro mammalian cell gene mutation assay (using L5178Y mouse lymphoma cells) was found to be positive with or without metabolic activation. This is suggestive of mutagenic activity; however, NTP (2003) noted that the increased mutation frequency was reported at cytotoxic concentrations. Thus, these results may be uncertain an d should be considered with other genotoxicity data and metabolism information (NTP, 2003).

• An in vitro Comet Assay (measuring deoxyribonucleic acid [DNA] damage) was performed with human leukocytes from venous blood drawn from unexposed a dult males. A significant increase in DNA damage was noted at the highest nPB doses (without metabolic activation). In the same study,

Toraason et al. (2006) reported that nPB did not induce DNA damage in vivo

, suggesting only limited evidence that nPB increased DNA damage in workers

at two facilities. Toraason et al. (2006) hypothesized that the most likely explanation for the disparity between in vitro and in vivo results is the high concentration (1 m illimolar [mM]) of nPB required to produce DNA damage in

vitro

.11 • An in vitro mammalian chromosome aberration assay (Organisation for Economic Cooperation and Development [OECD] Test 473) was performed with human peripheral blood lymphocytes (HPBLs) from one unexposed adult female (BioReliance, 2014; see Attachment B). A positive response was noted (both with and without metabolic activation) for structural chromosome aberrations, but the number of chromosome aberrations w as not reported (Table 2.5). Although these results are suggestive of DNA reactivity, this assay alone does not definitively indicate a mutagenic mode of action for nPB.

• The available in vivo test results were all negative or limited with resp ect to the potential for genotoxicity (see Table 2.5).

• Overall, the in vitro data are contradictory and inconclusive and the in vivo

results are negative. Thus, the existing data do not meet US EPA's indicators for determining a mutagenic mode of action for cancer:

Key data for a mutagenic mode of action may be evidence that the carcinogen or a metabolite is DNA reactive and/or has the ability to bind

DNA. Also, such carcinogens usually produce positive effects in multiple test systems for different genetic endpoints, particularly gene mutations

and structural chromosome aberrations, and in tests performed in vivo which generally are supported by positive tests in vitro

. (US EPA, 2005b)

• Thus, nPB may induce a carcinogenic response via another non

- mutagenic

mechanism. For instance, mutations or DNA damage identified in in vitro assays may be due to indirect mechanisms (e.g., cytotoxic exposures or damage to DNA repair genes, which predispose cells to background genetic alterations; US EPA, 2005b). Thus, the existing data are inconclusive (i.e., inconsistent and contradictory in vitro and in vivo test results) with regard to potential human carcinogenicity of nPB.

 T he tissues in which neoplastic lesions were observed in rodents from the NTP study (skin, intestine, and alveolar/bronchial cells) are known to have high cell

turnover rates. These neoplasms may have resulted from an indirect mechanism

such as chronic inf

lammation and cytotoxicity followed by regenerative proliferation, promoting spontaneous mutations (US EPA, 2005a; Cohen et al.

, 2004; Meek et al. , 2014; Hernandez et al. , 2009). In addition, NTP (2011) and Morgan et al. (2011) noted the presence of inflammatory Splendore

- Hoeppli

bodies in multiple tissues of male and female rats (including skin and peritoneum). Splendore

- Hoeppli bodies are associated with botryomycotic infections, and rats in the chronic bioassay were f ound to be positive for Pseudomonas aeruginosa (NTP, 2011). Thus, exposure to nPB in this study may have resulted in immunosuppression. Immunosuppression can elicit direct

cellular effects (cytotoxicity), promoting cellular regeneration, which can, in tu rn, lead indirectly to cancer formation (Hernandez et al. , 2009). Thus, there are plausible alternative non

- genotoxic mechanisms for the observed rodent tumors,12 suggesting that the results from the NTP study may have arisen as a secondary effect (e.g., cy totoxicity) from sustained exposure to elevated concentrations, rather than a direct mutagenic effect. Additional information is needed to

elucidate the mechanism of action for nPB.

 Finally, the exposure concentrations used by NTP (62.5

- 500 ppm) are sev eral

orders of magnitude greater than those modeled for ambient air for the general population (either by the petitioners or as presented in Section 3). Thus, the results of the NTP study and other existing mutagenicity data may be qualitative with regard to potential carcino genic effects, but not reliable for quantitative extrapolation from animals to humans. ”

EPA Response: Since the publication of t he NTP bioassay cited by the commenter (NTP 2011), the NTP publishe d its 13 th RoC (NTP 2014). In this report, the NTP concluded that there is sufficient evidence of carcinogenicity for 1

- bromopropane based on (1) skin tumors in male rats, (2) tumors of the large intestine in female and male rats, and (3) lung tumors in female mice. The report also cited malignant mesothelioma of the abdominal cavity and pancreatic islet tumors in male rats and skin tumors (squamous

- cell papilloma, keratoacanthoma, and basal

- cell adenoma or carcinoma) in female rats as supporting evidence. The NTP’s monograph for 1

- bromopropane addresses all of the data issues that the commenter raised (NTP 2013).

According to EPA’s Guidelines for Carcinogen Risk Assessment (U.S. EPA 2005a), an agent can be classified as “Likely to Be Carcinogenic to Humans” if it “has tested positive in animal experiments in more than one species, sex, strain, site, or exposure rou te, with or without evidence of carcinogenicity in humans”. Inconsistencies between how the data were interpreted by the NTP and how that same data might be interpreted under EPA’s Guidelines for Carcinogen Risk Assessment (U.S. EPA 2005a) were not identi fied ( see reference 6 in the proposed rule )

. The EPA Guidelines for Carcinogen Risk Assessment reference the NTP criteria for assessing individual studies in the assessment of carcinogenicity, stating “(c)riteria for the technical adequacy of animal carci nogenicity studies have been published and should be used as guidance to judge the acceptability of individual studies, e.g., NTP, 1984...” (pg. 2

- 16).

While EPA acknowledges that uncertainties exist when evaluating any agent, EPA agrees

with NTP’s assessm ent of the data and conclusions regarding the carcinogenicity of 1

- bromopropane. Indeed, according to U.S. EPA Guidelines for Carcinogen Risk Assessment (U.S. EPA 2005a) “The default option is that positive effects in animal cancer studies indicate

that t he agent under study can have carcinogenic potential in humans. Thus, if no adequate human or mode of action data are present, positive effects in animal cancer studies are a basis for assessing the carcinogenic hazard to humans.” EPA believes that the e valuation of the available data are consistent with EPA’s guidelines including EPA’s “Supplemental guidance for assessing susceptibility from early

- life exposure to carcinogens (Final)” (U.S. EPA 2005b).

T he NTP in its monograph of 1

- bromopropane (NTP 20 13), which supported the 13 th

RoC listing (NTP 2014), concluded the following:13

“Studies in vivo show that 1

- bromopropane can covalently bind to protein in exposed rats and occupationally exposed workers. The available data provide some support that 1

- bromopropane is genotoxic as it induced mutations in bacterial and mammalian cells and DNA damage in human cells. There is limited evidence that DNA damage was induced

in leukocytes from 1

- bromopropane

- exposed workers. 1

- Bromopropane did not induce

c hromosomal damage in exposed rodents (micronucleus induction assay) or gene

- cell mutations (dominant lethal mutation assay). Several known or postulated metabolites of

1

- bromopropane have been identified as mutagens and two, glycidol and propylene oxide (proposed), were shown to cause chromosomal and DNA damage in cultured mammalian

cells. Both metabolites caused chromosomal damage in cells from rodents exposed in

vivo , and propylene oxide induced DNA damage in cells from exposed workers. Three

oth er 1

- bromopropane metabolites (α

- bromohydrin, 3

- bromo

- 1

- propanol, and 1

- bromo

- 2

- propanol) were mutagenic or caused DNA damage in bacteria.”

EPA agrees with the NTP’s conclusions regarding the mutagenicity of 1

- bromopropane and its

metabolites. With the exception of the summary information provided by the commenter for one unpublished study, all of the studies cited by the commenter in their assessment of the mutagenicity data for 1

- bromopropane were cited by the NTP in their monograph for 1

- brom opropane (NTP 2013). Also, the commenter focused on the mutagenicity data for 1

- bromopropane but the data on the mutagenicity of the metabolites of 1

- bromopropane are an important part of the assessment as well. The summarized results of the unpublished study provided by the commenter do not change the conclusion regarding the mutagenicity of 1

- bromopropane and its metabolites.

Commenter: Halogenated Sol vents Industry Alliance, Inc. (HSIA )

Comment:

“ Substantial evidence is presented in the notice to sup port the conclusion that nPB

is known to cause or can reasonably be anticipated to cause cancer in humans. In addition, published studies indicate that nPB is neurotoxic, may cause r eproductive dysfunction, and is acutely or chronically toxic. A f ront

- page New York Times expose on March 31, 2013 graphically illustrated the public health threat posed by the use of

nPB. 1 Case studies have indicated severe neurotoxicity in workers exposed to nPB; many

of the case subje cts needed hospitalization and the effe cts may have been irreversible. 2

It is also noteworthy that in 2014 by the American Conference of Governmental Industrial Hygienists ("ACGIHJ') adopted a threshold limit value

- time

- we ighted average (TL VTWA) of 0.1 ppm for nPB. 3 This remarkabl y low TLV illust rates the relative hazard of nPB compared to the TLV s for chlorinated solvents used in the same or similar applications such as trichloroethylene (1 0 ppm), perchloroethylene (25 ppm), and methylene chloride (50 ppm). Moreover, the North Ca rolina Department of Labor issued

a Hazard Alert in 2014 that warned:

"1

- Bromopropane can harm both the nervous system and the reproductive system.14 It can damage the nervous system by interfering with nerve conduction, resulting in limb weakness, pain, numbness, and paralysis. It can cause reduced fertility and/or sterility in test animals, both male and female, and it can harm the developing fetus in pregnant female test animals. It will soon be tested to find out if it can cause cancer, as many s imilar chem icals do. Other harmful effects

include i rritation of the eyes and skin. " 4

Other environmental and public health agencies ha ve either regulated or proposed regulating nPB. The Occupational Safety an d Health Administration's H azard

Com m u nication Standard applies to nPB. Under this requirement, employers must provide health and safety information, including the TLV noted above, an d training to workers using nPB. 5 The European Union classifies nPB as R60 (may impair fertility) and R63 (po ssible risk of harm to the unborn chi ld) under its European Chemical

Su bst ances Information System. It also lists nPB as a Substance of V ery High Concern

un der its Regulation Registration, Evalua tion, Authorisation and Restriction of Chemicals (REACH). 6 A principal aim of REACH is ''to ensure a high level of protection of human

health and the environment from the risks that can be posed by chemicals. " 7

California regulates nPB under Propo sition 65, which lists nPB as a developmental/reproductive toxican t. 8 Pennsylvania lists nPB on its hazardous substance list, Rhode Island has regulated nPB as a toxic air contaminan t since 1980, and

Massachusetts requires facilities to report on their use of nPB and to conduc t toxics use reduction planning unde r its To xics Use Reduction Act.

Also potentially useful to EPA is a report on a study conduc ted to estimate the

health risk to workers exposed to nPB used as a cleaning solvent in Korean workplaces. 9

An exposure assessment revealed central tendency exposure (CTE) and reasonable maximum exposure (RME) levels of 82.1 and 214.8 mg/m 3 , respectively. For risk characterization, the nPB exposure concentrations for reproductive and developmental

toxici ties were calculate d as 2.8 and 8.5 mg/m 3 , and compared with the reference concentrations in the workplace. The CTE and RME hazard quotients (HQs) were, respectively, 29.4 and 77.0 fo r reproductive toxicity and 9.6 and 25.2 for developmental toxicity. The results of the ri sk asses sment indicated that the CTEHQs for both categories were higher than the acceptable risk val ue of 1, leading the authors to conclude that nPB may be co nsidered as harmful to workers.

Also relevant is a review article that includes a d ozen human cases that have been reported with symptoms and signs of toxicity to nPB, in cluding numbness and

diminished vibration sense in the lower extremi ties as well as ataxic gait. 10

Clearly, the scientific literature supports the addition of nPB to the list of

chemicals subject to reporting under EPCRA § 313.

1 http://www.nytimes.com/2013/03/31/us/osha

- emphasizes

- saftey

- health

- risks

- fester.html

. 2 See Majersik et al. , Severe Neurotoxicity Associated with Exposure to the Solvent 1

- Bromoprop ane (n

Propyl Bromide), Clinical Toxicology 45; 270

- 276 (2007).

3 http://www.acgih.org/resources/press/TLV2014list.htm15 4 http://www.nclabor.com/ os ha/etta/hazard_alerts/1

- Bromo prop ane.pdf. An earlier Hazard Alert was issued by the Occ upational Safet y and Health Administration and the National Institute for Occupational Safety

and Health; https:// www.osha.gov/Publications/OSHA_3676 .pdf.

5 29CF.R. § 1910.1200(g).

6 European Commission Joint Research Center, Ins titute for Health and Consumer Protection, European

Chemical Substa nces Information System, CAS# 1 04

- 96

- 5 and European Chemicals Agency, "Agreement

of the Member State Committee on the Identification of 1

- Bromopropane as a Substance of Very High
Concern," November 2012.

7 http://ec.eurgpa.eu/enterprise/sectors/chemicals/reach/ index_en .htm.

8 Cal ifornia Office of Environmental Health Hazard Assessment. Propo sition 65, Notice to Interested
Parties, December 3, 2004.

9 Moon HI, Shin, S, Byeon, SH., Exposure Monitoring and Health Risk Assessment of 1

- Bromopropane as

a C leaning Solvent in the Workplace , Hum Eco Risk Assess 21: 744

- 752 (20 15).

10 Ichihara et al. , Neurotoxicity of 1

- Bromopropane; Evidence fr om Animal Experim ents and Human

Studies, Journal of Advanced Research 3: 91

- 98 (April 20 12). ”

EPA Response: EPA agrees with the commenter’s statement that EPA provided s ubstantial evidence to support the conclusion that 1

- bromopropane is known to cause or can reasonably be anticipated

to cause cancer in humans

. EPA also agrees with the commenter’s conclusion that the scientific literature supports the addition of 1

- bromopropane to the EPCRA section 313 chemical list.

E PA acknowledges that there may be other toxicologica l effects that may also be a basis for listing. However, EPA believes the available cancer data are sufficient for adding 1

- bromopropane to the EPCRA section 313 chemical list.

Commenter: Anonymous Comment er 1

Comment:

“ Regarding the Evironmental (sic) Protection Agencys proposal to add 1

- Bromopropane to the list of toxic chemicals subject to reporting under section 313 of the EPCRA of 1986 and section 6607 of the PPA of 1990, I think this proposed rule should be put in place. According to Gak u Ichihara, researcher in the Department of Occupational and Environmental Health in Nagoya University, it was concluded that 1

- Bromopropane should be used carefully in the workplace, because it may be seriously neurotoxic to

humans in addition to its r eproductive toxicity. These conclusions were drawn after experimental research on rats. 1

- Bromopropane weakened the muscle strength of rat

limbs and deteriorated MCV and DL. Histopathological studies showed bubble

- like debris of myelin in the periphe ral nerve, preterminal swelling in the gracile nucleus, and irregular banding of muscle fibers in soleus muscle. In another study by Gaku Ichihara, neurologic abnormalities were actually observed in workers of a 1

- Bromopropane factory. Some of the resu lts were that workers reported reduced/complete loss of vibration sensation and lower values on neurobehavioral tests (forward and backward digit span, Benton visual memory test, etc.). The study summarized that exposure to 1

- Bromopropane produces adverse effects on peripheral sensory and motor nerves and the central nervous system in humans. Also, estimation of long

- term exposure levels is required to confirm the precise association between the health effects of 1

- Bromoprop ane16

and exposure levels. Because of this evidence, it is imperative that the EPA puts this proposed rule in place in order to protect workers who have to work with this product. ”

EPA Response: EPA agrees that 1

- bromopropane should be added to the EPCR A section 313 chemical list. EPA also acknowledges that there may be other toxicological effects (such as neurotoxicity) that may also be a basis for listing. However, the available cancer data are sufficient for adding

1

- bromopropane to the EPCRA sectio n 313 chemical list.

Commenter: Anonymous Comment er 2

Comment:

“ I agree with the proposed rule so long as the benefits substantially outweigh the costs. I believe it is important to consider how local businesses will be affected by the change. As the agency notes, there are no reports that show a relationship with cancer and 1

- Bromopropane in humans. There is only a foreseeable harm. And, if this rule is promulgated, there may be significant costs to local businesses, i.e., laundry services, that have to update or replace their equipment as well as significant costs and time spent in order to comply with the rule. Therefore, I ask the agency to seriously consider the cost/benefit analysis before promulgating the proposed rule. ”

EPA Response:

EPA’s cost

- benefit analysis was contained in the economic analysis for the proposed rule (Economic Analysis of the Proposed Rule to add 1

- Bromopropane to the EPCRA Section 313

List of Toxic Chemicals ), which was reference 8 in the Federal Register notice. The economic analysis contains a quantit ative estimate of the costs and a qualitative discussion of the benefits

of the rule. EPA considers the benefits of reporting under this rule to be primarily reflected by

the purposes served by reporting of information under EPCRA section 313. EPA believes the benefits provided by the information to be reported u nder this rule outweigh the costs.

With regard to l aundry services ( such as dry cleaners ) these facilities are not subject to

report ing under EPCR A section 313. E ven if such facilities were subject to reportin g , listing a chemical under EPCRA section 313 does not require covered facilities to update or replace any equipment. EPCRA section 313 only requires the reporting of release and waste manage ment
information , it does not impose any restrictions on the use of chemicals

.

References Cited in EPA Responses

NTP . 2011 . Technical Report on the Toxicology and Carcinogenesis Studies of 1

- Bromopropane (CAS No. 106

- 94

- 5) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). Toxicity Report

Series No. 564. NIH Publication No. 11

- 5906. Department of Health and Human Services, Public Health Service, Research Triangle Park, NC.

NTP. 2013. Report on Carcinogens Monograph on 1

- Bromopropane. Office of the Rep ort on Carcinogens, Division of the National Toxicology Program, National Institute of Environmental17

Health Sciences, U.S. Department of Health and Human Services. NIH Publication No. 13

– 5982, September 25, 2013

NTP. 2014. National Toxicology Program. Rep ort on Carcinogens, Thirteenth Edition. Released October 2, 2014. U.S. Department of Health and Human Services, Public Health Service,

National Toxicology Program, Research Triangle Park, NC 27709. (http://ntp.niehs.nih. gov/pubhealth/roc/roc13/index.html)

U.S. EPA. 2005a. Guidelines for carcinogen risk assessment. Risk Assessment Forum, Washington, DC , March 2005. EPA/630/P

- 03/001F.

U.S. EPA. 2005b. Supplemental guidance for assessing susceptibility from early

- life exposure to carcinogens (Final). Risk Assessment Forum, Washington, DC , March 2005. EPA/630/R

03/003F.

U.S. EPA. 2014. Summary Report of the State

- of

- the

- Science Workshop on Chemically

- induced Mouse Lung Tumors: Applications to Human Health Assessments. National Center for

Environmental Ass essment, Washington, DC , December 2014. EPA/600/R

- 14/002

.