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 20460
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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.

Commenter: Albemarle Corporation

The majority of comments provided by Albemarle are the same comments they submitted 

in response to the “Receipt 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 provided in a letter from Charles R. Nestrud of the law firm Chisenhall, Nestrud & Julian, 

P.A. dated June 10, 2015 (Nestrud 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 issues 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 consistency with the EPA 

Guidelines for Carcinogen Risk Assessment (U.S. EPA 2005a). Consistent with the EPA 

guidelines (U.S. EPA 2005a), the NTP 13th Report on Carcinogens (RoC) (NTP 2014) evaluates 

the scientific literature and publicly available, peer-reviewed 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 potential hazard associated with chemicals but does not 

establish the exposure conditions that would pose cancer risks to individuals. In the 13th RoC, 

the NTP classified 1-bromopropane as “reasonably anticipated to be a human carcinogen.” The 

conclusions of the NTP 13th 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-

bromopropane 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 EPCRA 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 Petition to Add n-Propyl Bromide to the List of Hazardous 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 chemicals list, EPA has addressed these comments as 

well.
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Comment: Nestrud 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 proposed 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 13th RoC which was 

released on October 2, 2014. EPA’s evaluation of the data used to support the findings for 1-

bromopropane was conducted shortly after the release of the 13th 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 facilities 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 13th RoC data and findings for 1-bromopropane (reference 6 in the 

propose rule), or specific to the NTP 13th 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 

information that EPA submitted to support the proposed rule that the commenter believes is out 

of date, incorrect, or insufficient to support the proposed rule. Comments regarding the available 

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

Comment: Nestrud letter

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

chemicals for additions to the list of toxic chemicals. This included a toxicity and 

production volume screen, and a hazard evaluation based on the initial screen. Addition 

of Certain Chemicals; Toxic Chemical Release Reporting; Community Right-to-Know; 

Final Rule (59 Fed. Reg. No. 229; Doc. No. 94-29376, November 30, 1994; OPPTS400082B.

Toxicity Screen. Through the 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 information to 

support assigning a "high 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 1994 chemical expansion rulemaking to evaluate large numbers of chemicals for 

potential addition. These screening criteria are not the criteria used to determine whether or not 
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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. Such 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 available cancer data and based on the classification by the NTP in their 13th

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 proposed 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 classify 1-bromopropane as a high priority 

for listing. In fact, the NTP’s 6th RoC was a primary source reviewed for chemicals for potential 

addition (59 FR 1789, January 12, 1994). As previously noted, the commenter did not provide 

any comments specifically on the NTP’s classification of 1-bromopropane as “reasonably 

anticipated to be a human carcinogen” in the 13th RoC nor did they provide any comments on 

EPA’s evaluation of the NTP cancer data and classification as provided in reference 6 of the 

proposed rule (80 FR 20189, April 15, 2015). 

Comment: Nestrud 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 Form Rs and 14 Form As) from 23 different industry sectors
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will be filed for 1-bromopropane. Therefore, EPA has determined that there is sufficient 

production and use of 1-bromopropane such that reports will be filed. As previously noted, the 

commenter provided no specific comments on EPA’s economic analysis. Certain 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 EPA’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 carcinogens to the EPCRA section 313 chemical list:

“Section 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: Nestrud 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 identified 

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 that 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 that 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 13th

RoC. 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-bromopropane. 

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.” 
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EPA believes the cancer data for 1-bromopropane sufficiently 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 pollutant

(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 addressed elsewhere in this document. 

With regards to 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 chemical list. EPA did not base the proposed 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 or 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 chemicals under EPCRA section 313(d)(2)(B). As 

EPA stated in the proposed rule:

“EPA considers chemicals 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 

consider 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 does not believe that an exposure assessment is necessary or appropriate for 

determining whether 1- bromopropane meets the criteria of EPCRA section 

313(d)(2)(B).”

EPA disagrees 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 extensive cancer data that support this addition as discussed 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 supporting 
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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 concentrations, 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 aforementioned 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 female 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 chemicals (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, rats, and humans with respect to lung 

physiology, metabolism (pharmacokinetics and pharmacodynamics), and

genotoxicity (US EPA, 2014).
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 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 or 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 

appropriate, 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 the 

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 

characterizing 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 technical workshop on the state-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 Risk 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.”
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The NTP 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 

understood 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 

induce 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 multiple 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 modes of action for 1-bromopropane-induced 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 classified 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 Corp. 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:
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 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 mutagenicity 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 

negative. 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 assay 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 and 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 adult 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 millimolar [mM]) of nPB required to produce DNA damage in 

vitro.
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• 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 was 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 respect 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.

 The 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 inflammation 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 found 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 turn, 

lead indirectly to cancer formation (Hernandez et al., 2009). Thus, there are 

plausible alternative non-genotoxic mechanisms for the observed rodent tumors, 
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suggesting that the results from the NTP study may have arisen as a secondary 

effect (e.g., cytotoxicity) 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 several 

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 carcinogenic effects, but not reliable for quantitative 

extrapolation from animals to humans.”

EPA Response:

Since the publication of the NTP bioassay cited by the commenter (NTP 2011), the NTP 

published its 13th 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 route, 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 identified (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 carcinogenicity 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 assessment 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 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.” EPA believes that the evaluation 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).

The NTP in its monograph of 1-bromopropane (NTP 2013), which supported the 13th

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 

chromosomal 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 

other 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-

bromopropane (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 Solvents Industry Alliance, Inc. (HSIA)

Comment:

“Substantial evidence is presented in the notice to support 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 reproductive 

dysfunction, and is acutely or chronically toxic. A front-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 subjects needed hospitalization and the effects 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-weighted 

average (TL VTWA) of 0.1 ppm for nPB.3 This remarkably low TLV illustrates the 

relative hazard of nPB compared to the TLVs for chlorinated solvents used in the same or 

similar applications such as trichloroethylene (10 ppm), perchloroethylene (25 ppm), and 

methylene chloride (50 ppm). Moreover, the North Carolina 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 similar chemicals do. Other harmful effects 

include irritation of the eyes and skin."

4

Other environmental and public health agencies have either regulated or proposed 

regulating nPB. The Occupational Safety and Health Administration's Hazard 

Communication Standard applies to nPB. Under this requirement, employers must 

provide health and safety information, including the TLV noted above, and training to 

workers using nPB.5 The European Union classifies nPB as R60 (may impair fertility) 

and R63 (possible risk of harm to the unborn child) under its European Chemical 

Substances Information System. It also lists nPB as a Substance of Very High Concern

under its Regulation Registration, Evaluation, 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 Proposition 65, which lists nPB as a 

developmental/reproductive toxicant.8 Pennsylvania lists nPB on its hazardous substance 

list, Rhode Island has regulated nPB as a toxic air contaminant since 1980, and 

Massachusetts requires facilities to report on their use of nPB and to conduct toxics use 

reduction planning under its Toxics Use Reduction Act. 

Also potentially useful to EPA is a report on a study conducted 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/m3, respectively. For risk 

characterization, the nPB exposure concentrations for reproductive and developmental 

toxicities were calculated as 2.8 and 8.5 mg/m3, and compared with the reference 

concentrations in the workplace. The CTE and RME hazard quotients (HQs) were, 

respectively, 29.4 and 77.0 for reproductive toxicity and 9.6 and 25.2 for developmental 

toxicity. The results of the risk assessment indicated that the CTEHQs for both 

categories were higher than the acceptable risk value of 1, leading the authors to conclude 

that nPB may be considered as harmful to workers. 

Also relevant is a review article that includes a dozen human cases that have been 

reported with symptoms and signs of toxicity to nPB, including numbness and 

diminished vibration sense in the lower extremities 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-Bromopropane (nPropyl Bromide), Clinical Toxicology 45; 270-276 (2007).

3

http://www.acgih.org/resources/press/TLV2014list.htm
15

4

http://www.nclabor.com/osha/etta/hazard_alerts/1-Bromopropane.pdf. An earlier Hazard Alert was issued 

by the Occupational Safety 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, Institute for Health and Consumer Protection, European 

Chemical Substances Information System, CAS# 104-96-5 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 California Office of Environmental Health Hazard Assessment. Proposition 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 Cleaning Solvent in the Workplace, Hum Eco Risk Assess 21: 744-752 (2015).

10 Ichihara et al., Neurotoxicity of 1-Bromopropane; Evidence from Animal Experiments and Human 

Studies, Journal of Advanced Research 3: 91-98 (April 2012).”

EPA Response:

EPA agrees with the commenter’s statement that EPA provided substantial 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. 

EPA acknowledges that there may be other toxicological 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 Commenter 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 Gaku 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 reproductive 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 peripheral 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 results 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-Bromopropane 
16

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 EPCRA 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 section 313 chemical list.

Commenter: Anonymous Commenter 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 quantitative 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 under this rule outweigh the costs.

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

reporting under EPCRA section 313. Even if such facilities were subject to reporting, 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 management 

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 Report on 

Carcinogens, Division of the National Toxicology Program, National Institute of Environmental 
17

Health Sciences, U.S. Department of Health and Human Services. NIH Publication No. 13–5982, 

September 25, 2013

NTP. 2014. National Toxicology Program. Report 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/R03/003F.

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 Assessment, Washington, DC, December 2014. EPA/600/R-14/002.