UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

EPA Response to Comments Received from the Submitter of TSCA Premanufacture 

Notice (PMN) P-14-260 regarding EPA's Risk Assessment and Derivation of the 

Occupational Exposure Limit for the Chemical Substance Reported in P-14-260. 

Date of document: Apri I 20, 20 15 

TABLE OF CONTENTS 

BACKGROUND ..................................................................... ....... ........... ...................................... 2 

AMPAC-I-lALOTRON COMMENTS .................................................................................... 2 

1.1 Comment n Interspecies Uncertainty Factor. ............ ............. • ...................................... 2 • 

1.1. I Cornrnent 1 ......................................... .......... ......................... ..................................... 2 

1.1.2 Response to Cornn1ent 1 ............................................................................................ 2 

1.2 Comment 2 on Intraspecies Uncertainty Factor. .. ........ .... ................................................. 3 

1.2.1 Comment 2 ................................................................................................................. 3 

1.2.2 Response to Co1nn1ent 2 ............................................................................................ 3 

1.3 Comment 3 on Dermal Exposure ..................................................................................... .4 

1.3.1 Comn1ent 3 ................................................................................................................. 4 

1.3.2 Response to Comment 3 ................................................................ ... ........................ .4 

1.4 Comment 4 on Selection of NOA EL ............................................................................... .4 

1.4.1 Con1ment 4 ........................ ........ .......... ....................................................................... 4 

1.4.2 Response to Con1ment 4 ............................................................................................ 4 

1.5 Comment 5 on Allowable Exposure Limit ....................................................................... 5 

1.5. 1 Co1nn1ent 5 .............................................................................................. ................... 5 

1.5.2 Response to Comn1ent 5 ............................................................................................ 5 

1.5.2. 1 Exposure Com111ents .......... ................................................................................. 5 

1.5.2.2 Question about EPA derivation of POD ............................................................. 7 

1.5.2.3 Allowable worker exposure limit ....................................................................... ? 

2 REFERENCES ................... .............. ........... ................................... ... ................................. ... 10 

LIST OF TABLES 

Table 1-1 Sunrn1ary of Postnatal Survival (%per litter) ................................................................. 5 

LIST OF FIGURES 

Figure 1- 1 P-14-0260 structurc ........................................................................................................ 2 

Figure 1-2 Calculation of human exposure variables ............................... ................ ....................... 8 

Internet Address (URL) • http://www.cpa.gov 

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2 

BACKGROUND 

On February 2, 2015 American Pacific Corp. (AMPAC)-Halotron held a conference call with 

EPA staff to discuss the risk assessment for P-1 4-0260. On February 13. 2015 they submitted a 

letter to EPA requesting that EPA re-consider 5 key items. This paper is a response to the 5 

items. 

P-14-0260 is 2- Bromo-3,3,3-Trifuoropropene (BTP) 

Br 

F")~ F-1 

F 

Figure 1-1 P-14-0260 structure 

AMPAC-HALOTRON COMMENTS 

1.1 Comment 1 on Interspecies Uncertainty Factor 

1.1.1 Comment 1 

Use of an inter-species uncertainty factor of 3 based on the submitted December 20 14 Skaggs 

report and contrast between human and rat partition coefficients. 

1.1.2 Response to Comment 1 

Agree. The default interspecies uncertainty factor (UF) 10 is generally considered to have 

pharmacokinetic and pharmacodynamic components that contribute to the uncertainty. Each 

component is accorded a factor of about 3 (actually 3.16). Where information allows a more 

precise estimation of the contribution of the component, the component's contribution may be 

reduced to I . 

The submitter argues that relative rat and human blood:air partition coefficients of BTP can be 

used to adjust the Point of Departure (POD) concentration in humans. The Skagg's report (20 14) 

states: 

"The blood:air partition coefficient of BTP in humans (0.21) is a/actor o.f2 lower than the 

blood: air partition coefficient measured in rats (0.52). A higher blood: air partition coefficient 

in rats, indicates that BTP is more soluble in rat blood, so BTP will more easily diffuse into the 

rat blood stream with a final equilibrium that will likely be twice that in humans. " 

US EPA (20 11) states: "Jn the RfC Methods, the DAF derivation.for ER effects is based more on 

science policy than on an empirical procedure. Further, this policy is hi-level; (I) where if Hblg 

values are unknown the default value for (Hb;g},i I (l-h1r}H = 1; (2) [( (Hblg)A is greater than 

(Hblg)H then a de.fault value of 1 is also used.., 
3 

For BTP, the rat blood:air partition coefficient is greater than the human value by a factor of2.5. If this were used to calculate the human POD, the human POD would be 2.5 times greater 

than the rat value. EPA policy is to use an adjustment factor of 1 in this case. However, since this 

procedure allows for a more precise estimation of the human POD concentration, the 

pharmacokinctic component of the equation can be reduced from 3 to 1. 

1.2 Comment 2 on Intraspecies Uncertainty Factor 

1.2.1 Comment 2 

Use of an intra-species uncertainty factor of 3 based on the san1e Skaggs report and EPA 

precedence. 

1.2.2 Response to Comment 2 

Reject. The Skaggs 20 14 report cited a number of arguments about why the intraspecies UF 

should be reduced from 10 to 3. 

• Workplace exposures involve healthy worker populations that do not involve sensitive 

individuals. 

o The human adult female and fetus are the susceptible populations. Women can 

work in chemical plants. Therefore, susceptible populations are not excluded from 

the workforce. 

• Workers are predominantly mal e and toxicity studi es indicate a higher No Observed 

Adverse Effect Level (NOAEL) for males than females. 

o Women can work in chemical plants. Therefore, they must be considered in any 

risk assessment. 

• "The RfC intrahuman variability uncertainty factor is intended to protect for potential 

''unobserved" reproductive medical conditions (e.g., decreased sperm motility, 

amenorrhea and ovulation dysjimction) that are known to exist among otherwise healthy 

populations. However, because we are primarily concerned about exposures in the 

·workplace, not exposures to the general population, ... we believe ii is appropriate to use 

a lower uncertainty factor of 3 instead of the fit!! RfCs uncertainty factor of 10 for intrahuman variability. " 

o The workpl ace exposure would potenti all y expose pregnant women. Therefore 

this argument is not valid. 

• " ... and because exposures would not be continuous (2./ hours/day) in a workplace 

selling (8 hours/day, 5 days/week), we believe ii is appropriate to use a lower uncertainty 

factor of 3 instead of the full R}Cs uncertainty factor of I 0 for intra-human variability." 

o The worker scenarios are for 4 days a week exposure and I 0 hours a day. The 

animal studies were conducted for 7 days a week and 6 hours a day. The disparity 

in exposure regimen is not that great. The extrapolation is valid. 

• The EPA Office of Air and Radiation used an intraspecies UF of 3 for n-propyl bromide 

and 1 for C7 fluoroketone. 

o PMN exposure results in decreased survival of offspring at the Low Observed 

Adverse Effect Level (LOAEL) and higher concentrations. The effects are severe 

and the mode of action is unknown. Without this knowledge there are insuffi cient 

grounds to .decrease the default UF of 10. 
4 

o The SNAP Program agrees the intraspecies UF for this PMN should be 10. 

1.3 Comment 3 on Dermal Exposure 

1.3.1 Comment 3 

Determination by EPA that dermal exposure is not a factor for this PMN based on use and 

physical properties. 

1.3.2 Response to Comment 3 

Agr ee. This comment mainly addresses the EPA use of dermal exposures to workers. The 

submitter argues that the vapor pressure is so high that this exposure will not occur. EPA agrees, 

dermal exposure has been removed from the worker scenarios. 

1.4 Comment 4 on Selection of NOAEL 

1.4.1 Comment 4 

Use of a NOA EL/POD of 100 ppm in the derivation of the adverse effect level (AEL) based on 

the submitted information (Skaggs paper), the WIL Research report conclusion, and peer review 

by Dr. York. 

1.4.2 Response to Comment 4 

Disagree. 

The reproductive effects study report stated "'Test substance-related, lower (not statistically 

sign(ficant) postnatal survival was noted in the JOO and 175 ppm groups compared lo the 

concurrent control group during postnatal day (PND) 0-1, 1-4, andfrom birth to PND 4; the 

values in the 175 ppm group were below the minimum mean values in the WIL Research 

historical control data, and 1 female in this group (no. 91654) had a total lifler loss on PND 2. 

There.fore, the postnatal survival at this exposure level was considered adverse. The postnatal 

survival values in the JOO ppm group were within the range of values in the WIL Research 

historical control data, and therefore were considered within normal limits and not adverse. " 

Postnatal survivals are shown in Table 1-1. The postnatal surviva l rates show a dose-response of 

decreasing survival with increasing exposure concentration. While the 84.1 % survival from birth 

to PND 4 at I 0 I ppm is with the low range of the historical control value of 83.8%, it is just 

barely within that range and is in a continuum of decreasing survival with increasing exposure 

concentration. Therefore, l 0 I ppm is considered adverse. The NOA EL for postnatal survival is 

50 ppm. The dose response continuum is also re nected in increased gestation lengths and 

interventricular septa! defects in pups found dead. 
5 

Table 1- 1 Summary of Postnatal Surviva l (% per litter} 

Parameter 0 ppm 50 ppm IOI ppm 174 ppm WIL-HC* 

Mean (Range} 

PND 0 (relative to 96.5 98.0 95.2 95.4 98.0 (93.3-

number born) 100.0) 

PND 0 to PND I 99.2 98.1 96.1 91.7 98.7 (94.6-

100.0} 

PND I to PND 4 97. 1 95.9 91.7 76.5 98.4 (87.0-

99.8} 

Birth to PND 4 92.8 "92.1 84.1 67.9" 95.3 (83.8-

98.7) 

* = WIL historical control data 

The EPA SNAP Program agrees with the selection of 50 ppm as a NOAEL. 

1.5 Comment 5 on Allowable Exposure Limit 

1.5.J Comment 5 

Determination of an allowable worker exposure limit, 8-hr time weighted average, of 11 ppm or 

above. 

1.5.2 Response to Comment 5 

Disagree 

This response will be subdivided into three sections to address: 

- Exposure comments 

-Question about EPA derivation of POD 

-Allowable worker exposure limit 

1.5.2.1 Exposure Comments 

EPA revised the occupational exposure assessment taking into account your requests; this 

revised assessment includes revised values for exposure concentration. duration and frequency. 

EPA carefully reviewed the monitoring studies that you provided, commented on them and 

discussed them with you on three occasions via te lephone or email exchange. He assessed 

exposure concentration at your site and at your customer site and the associated duration and 

frequency of exposure based on these studies and his discussions you. The revised assessment 

results are discussed below. 

EPA assessed exposure concentration at your site to be 2. 1 ppm 10 hr time-weighted average 

(TWA), whi ch is the average airborne concentration that is reported in the monitoring study of 

the PMN chemical dated 12/8/14. This level is associated with engineering controls comprising 

sampling in a closed bottle and a nitrogen purge prior to disconnect which avoids spilled material. 

EPA did not adopt the value you recommend in Table I of your letter of2/l3/l 5, which is 0.62 

ppm. because the basis of this extrapolated value is not clearly described in the monitoring study. 

In accordance with his discussion with you, EP /\ assessed exposure duration to be I 0 hrs per day 

and frequency to be 4 consecutive days per month, 12 months a year or 2 consecutive days twice 

per month, 12 months per year (or 48 days per year.) Note that exposure level for an 
6 

inexperienced operator is higher, but the value is not clearly reported in the study, and you 

informed EPA that an inexperienced operator would quickly learn and exposure level would 

decli ne. 

EPA assessed exposure concentration at your customer site to be 6.6 ppm I 0 hr TWA. This 

value was derived from exposure concentration va lues reported in your report dated 11127/ 14. 

The derivation of this value is as follows: 

1. Average airborne concentration of HCFC 123 (Halotron I) outside of booth is 3.2 ppm 

according to submitter report dated 11127114, pg. 40. Maximum avg. concentration of same 

inside of booth is 31.5 ppm (pg. 39 of report). Maximum reported values were adopted for a 

conservative assessment. 

2. Time spent with the door of booth open and operator working in the booth was estimated 

to be 12.5% of total time as follows: 

• 300 bottles are filled per shift according to our discussion; 

• . time spent with door ope.n is about 30 sec. accordil)g to our discussion; 

therefore, total time with door open = 300 * 0.25 min = 75 min. Fraction of time spent 

with booth door open = 75 min I ( l 0 hr* 60 min /hr ) = 0.1 25 

3. Therefore, exposure concentration assessed as follows: 10 hr TWA concentration = 3 1.5 

* 0.125 + 3.2 * 0.875 = 6.74 ppm ofHCFC 123 (Halotron 1). 

4. EPA adjusted this value for physical properties of the PMN chemical based on the 

following assumptions: 

a. The volumes of liquid that is released during disconnection of feed line to bottle is 

equivalent for Halotron 1 and the PMN chemical (based on EPA 's discussion with you). 

b. All of the released Halotron l liquid evaporates based on the observations reported in 

relation to the exposure monitoring conducted at your site. All of the PMN chemical liquid that 

is released is assumed to evaporate as well because the VP of the PMN chemical is similar to the 

VP ofl-ICFC 123. The above assumption remains valid even if the evaporation rate of the PMN 

chemical is lower due to a slightly lower vapor pressure because any PMN chemical that does 

not evaporate immediately will eventually evaporate as was observed during the exposure 

monitoring at your site. 

c. Airborne concentration of the chemical is at a steady state. This is certainly the case 

outside the booth. 

d. Based on these assumptions, a mass balance on the chemical is as follows: volume 

re leased * liquid density = volumetric ventilation rate* concentration of chemical in ppm * 

density of chemi cal vapors. Applying this equation to both HCFC 123 and the PMN chemical 

and applying the ideal gas Jaw to the density of the chemical vapors, the following is deri ved: 

Concentration of PMN chemical = concentration of HCFC 123 * ratio of I iquid density of PMN 

chemical to HCFC 123 * ratio ofmol wt ofHCFC 123 to PMN chemical. ppm of PMN 

chemical = 6.7 ppm* (1653 kg/m3 /1476 kg/m3) * (152.93 I 174.95) = 6.6 ppm. 

EPA did not account adjust the Harleton 1 monitoring results using the multiplier of 0.45 that 

you recommended due to the fo llowing reasons: . . 
7 

a. According to your report, this value is highly uncertain and the experimental results do 

not support any values other than simply a value that is less I, which means that a value equal to 

1 is the upper I imit and is appropriate for a conservative assessment. EPA did not adjust the 

Halotron I results and therefore essentially used a value of I. 

b. Even if the value you had reported were sufficiently accurate, this value is site-specific 

and not applicable to your customer's site. For example, natural convection, or the flow of 

released PMN chemical vapor downward due to heavier density, can only occur if air currents 

arq sufficiently low but that ooes not appear to be the Gase at your customer's it~. Two fans are 

reported to be directed at the booth where monitoring occurred. 

Finall y, in accordance with EPA's discussion with you, exposure duration was assessed to be 10 

hr per day and exposure frequency was assessed to be I 00 days total comprising 2 weeks per 

month and 4 consecutive days per week. 

1.5.2.2 Question about EPA derivation of POD 

The submitter question how the worker POD of 2,055 mg/day is related to the 8,1 34 mg/day in 

the (ollowing sentence. They c;ilso questioned how these.are used in Table 4-2. Th~ 2,055 mg/day 

number is the correct value and was used in Table 4-2 to calculate the Margin of Exposure 

(MOE). The value of 8, 134 mg/day is not correct. The entire derivation of values has been 

rewritten to refl ect new exposure values and the approach revised to be more transparent. 

1.5.2.3 Allowable worker exposure limit 

The risk assessment for P-14-0260 has been revised to reflect the exposure information provided 

by the submitter and EPA's evaluation, revised uncertainty factors based upon the submitter's 

comments and a more transparent approach to the derivation. The submitter talked about an 8 

hour TWA but the revised exposure shows a I 0 hour workday for the workplace. 

A rat reproductive effects study NOAEL for decreased postnatal survival and increased gestation 

length is 50 ppm for 6 hours/day/7 days a week. This will be used as the Point of Departure 

(POD) for assessing repeated exposure risk. 

The acceptable MOE is 30 based upon the following rationale: 

The rat and human blood:air coefficients are 0.52 and 0.21 respectively. This means the 

human POD would likely be approximately 2.5 times the rat POD. However, EPA policy 

is to use a dosimetry adjustment factor of I when the rat blood:air coeffici ent is greater 

than the human. Since there is infom1ation to inform the pharrnacokinetic component of 

the interspecies UF and the selection of the human POD is conservative, the interspecies 

UF is reduced from 3 to I 0. 

There are no data no human variability in response to exposure to the PMN. The 

intraspecics UF is I 0. 

The composite MOE is the factor of the two UFs above or 3 * 10 = 30. 

The rat NOAEL is 50 ppm for 6 hours exposure for 7 days per week exposure. The health effects 

concentration (HEC) from the rat study is 12.5 ppm. Note that the HEC represents a 24 hour 

TWA for 7 days exposure in a resting human. Worker exposures are for I 0 hours per day for 4 

days per week. Tl~ e HEC adjusted for 4 day.s exposure is 2 l.9 ppm (l-!ECAoJ). 
8 

The HEC for the worker scenario is 11.9 ppm (HECscENARlo). This is lower than the 2 1.9 ppm 

HECADJ noted above because the worker is assumed to breath 10 m3 in 8 hours (equivalent to 30 

m

3 for 24 hours) whereas the i.:IEDADJ is based upon a resting breathing rate of 16.3 m3 

per day 

(The Exposure Factors Handbook gives breathing rates per day for age ranges {mean and 95th 

percentile} of the human population. The greatest mean value of 16.3 m3 per day is for age 16 to 

<21 ). The HECscENARIO was ca lculated by multiplying the HECAnJ by the ratio of the (resting 

breathing rate of 16.3 m

3 

per day)/(worker breathing rate of30 m

3 

per day). 

Note that the HECscENARIO is a 24 hour TWA. The TWA used in MOE calculations will be 

adjusted to the concentration appropriate to the duration under consideration. For I 0 hours of 

exposure for 4 days per week of exposure the 10 hour TWA is 28.5 ppm. Divided by a total UF 

of 30 the acceptable worker exposure is 0.95 ppm. 

ENTER VARIABLES INTO YELLOW CELLS· Exam le Is minutes but ou can uae hours 

'1f (H,.0 )Al(H09(H > 1 entM 1 lor both (H09( values 

Figure 1-2 Calcula tion of huma n ex posure va riables 

EQUATIONS 

1. Calculate HEC 

Note. In this example the (Cxt) expression is divided by 24 hours. If this is the case make sure 

that the t units are in hours. 

The C and t refer to the concentration and d uratio n in the animal experiment. 

Equation 1 Calcluate HEC from animal data 

H EC=(Cxt)-7·24 

2. Determine HECAo.1 - Adjust 1-IEC for Days of Exposure 

Equation 2 Adjust HEC fo r diffe r ences in d ays of exposure/week in animals and 

humans 

HEC_AD}=HECx(DAYS_ANIMAL+DAYS_HUMAN) 

3. Determine HECsc£NA R10 - Adjust HECAoJ fo r Scena rio Breathing Rate 

Equation 3 Adjust HEC for differences in breathing rates between the human at 

rest and in the specific scena r·io 

HEC_SCENARIO=HEC_AD}x(RESP _RESTING+RESP _SCENARIO) 
9 

4. Adjust HECsrnNARIO for Scenario Duration 

Equation 4 Determine concentration for the scenario duration 

C_SCENARIO=HEC_SCENAR/O x(24 hrs-7-t_SCENARIO ) 

5. Adjust the HEC for Differences in Blood:Gas Partition Coefficients 

Equation 5 Calculation of DAF 

DAF=(H_(blg) )Al(H_(blg) )H 

Equation 6 Correction for blood:gas partion coefficient differences 

Keel _(SCENARIO-BG))=(C_SCENARIO )xDAF 

VARIABLES AND ABBREVIATIONS 

Definition of Variables • 

C = Concentration in ppm or mg/m3

. Use same units throughout calculations. 

CscENARIO = Concentration for the duration under consideration in the specific human exposure 

see nano. 

CscENARIO-BG = CscENARIO corrected for differences in the blood:gas partition coefficients. 

OAF = Dosimetric adjustment factor. 

DA YSANIMAL = Days of week the animal was exposed. 

DA YS11uMAN = Days of week a human is exposed in the specific scenario. 

(Hhtg )A = Blood gas partition coefficient animal. 

(Hbtg )H = Blood gas partition coeffici ent human. 

HEC = Human Equivalent Concentration for the POD. This is a 24 hour a day value. 

HECAoJ = The HEC for the POD adjusted for differences in number of days exposure per week 

between animal and human exposure scenarios. 

HECscENARIO =The HECAoJ for the POD adjusted for differences in the resting breathing rate 

and the scenario breathing rate. 

k = Constant in Haber's rule equation of C * t = k. 

MOE= Margin of Exposure 

POD= Point of Departure 

RESPRESTING = Respiratory rate in a human at rest. · 

RESPscENARIO = Respiratory rate in a human in the scenario under consideration. 

t = Duration of exposure in minutes or hours. Use same units throughout calculations. 

tscENAR IO = Duration of the of the speci fie human exposure scenario. Use same units throughout 

calculations. 
10 

2 REFERENCES 

Skaggs, SR. 2014. Derivation of a Proposed Occupational Exposure Limit for 2 - Bromo - 3,3,3 

- Trifluoropropene. Universal Technical Services, Inc. 

US EPA. 2011. STATUS REPORT: Advances in Inhalation Dosimetry for Gases with Lower 

Respiratory Tract and Systemic Effects. EP A/600/R-l l /067. . .